Beta3 adrenergic agonists

ABSTRACT

The present invention relates to a β 3  adrenergic receptor agonist of formula I:  
                 
 
     or a pharmaceutical salt thereof; which is capable of increasing lipolysis and energy expenditure in cells and, therefore, is useful for treating Type II diabetes and/or obesity. The compound can also be used to lower triglyceride levels and cholesterol levels or raise high density lipoprotein levels or to decrease gut motility. In addition, the compound can be used to reduced neurogenic inflammation or as an antidepressant agent. Compositions and methods for the use of the compounds in the treatment of diabetes and obesity and for lowering triglyceride levels and cholesterol levels or raising high density lipoprotein levels or for decreasing gut motility are also disclosed.

[0001] This application claims the benefit of U.S. Serial Nos.60/217,965; 60/241,614; and 60/292,988.

FIELD OF THE INVENTION

[0002] The present invention is in the field of medicine, particularlyin the treatment of Type II diabetes and obesity. More specifically, thepresent invention relates to β₃ adrenergic receptor agonists useful inthe treatment of Type II diabetes and obesity.

BACKGROUND OF THE INVENTION

[0003] The current preferred treatment for Type II, non-insulindependent diabetes as well as obesity is diet and exercise, with a viewtoward weight reduction and improved insulin sensitivity. Patientcompliance, however, is usually poor. The problem is compounded by thefact that there are currently no approved medications that adequatelytreat either Type II diabetes or obesity.

[0004] One therapeutic opportunity that has recently been recognizedinvolves the relationship between adrenergic receptor stimulation andanti-hyperglycemic effects. Compounds that act as β₃ receptor agonistshave been shown to exhibit a marked effect on lipolysis, thermogenesisand serum glucose levels in animal models of Type II (non-insulindependent) diabetes.

[0005] The β₃ receptor, which is found in several types of human tissueincluding human fat tissue, has roughly 50% homology to the β₁ and β₂receptor subtypes yet is considerably less abundant. Stimulation of theβ₁ and β₂ receptors can cause adverse effects such as tachycardia,arrhythmia, or tremors. An agonist that is selective for the β₃ receptorover the β₁ and β₂ receptors is, therefore, more desirable for treatingType II diabetes or obesity relative to a non-selective agonist.

[0006] However, recent studies have suggested the presence of anatypical beta receptor associated with atrial tachycardia in rats (Br.J. of Pharmacol., 118:2085-2098, 1996). In other words, compounds thatare not agonists of the β₁ and β₂ receptors can still modulatetachycardia through activation of a yet to be discovered β₄ or throughsome other unknown pathway.

[0007] A large number of publications have appeared in recent yearsreporting success in discovery of agents that stimulate the β₃ receptor.Despite these recent developments, there remains a need to develop aselective β₃ receptor agonist which has minimal agonist activity againstthe β₁ and β₂ receptors.

SUMMARY OF INVENTION

[0008] The present invention relates to a compound of formula I:

[0009] wherein:

[0010] A¹, A² and A³ are carbon or nitrogen provided that only one ofA¹, A² and A³ can be nitrogen;

[0011] Het is an optionally substituted, optionally benzofused 5 or 6membered heterocyclic ring;

[0012] R¹, R^(1a) and R^(1b) are independently H, halo, hydroxy, C₁-C₆alkyl, C₁-C₆ alkoxy, C₁-C₄ haloalkyl, or SO₂(C₁-C₆ alkyl);

[0013] R² is H or C₁-C₆ alkyl;

[0014] R³ is H or C₁-C₆ alkyl;

[0015] R⁴ is H or C₁-C₆ alkyl;

[0016] or R³ and R⁴ combine with the carbon to which both are attachedto form a C₃-C₆ cyclic ring;

[0017] or R⁴ and X¹ combine with the carbon to which both are attachedto form a C₃-C₈ cyclic ring;

[0018] or R⁴ combine

the carbon to which both are attached, and the phenyl group to which X¹is attached to form:

[0019] wherein:

[0020] n and m are independently 0, 1, 2, or 3 provided that the sum ofn+m is≦4 and that R³ is H;

[0021] X is OCH₂, SCH₂ or a bond;

[0022] X¹ is a bond or a C₁-C₅ divalent hydrocarbon moiety;

[0023] x² is O, S, NH, NHSO₂, SO₂NH, CH₂ or a bond; and

[0024] X³ is optionally substituted phenyl or an optionally substituted5 or 6 membered heterocyclic ring; or a pharmaceutical salt thereof.

[0025] The present invention also relates to processes for preparing, aswell as novel pharmaceutical formulations containing, a compound offormula I. In another embodiment, the pharmaceutical formulations of thepresent invention may be adapted for use in treating Type II diabetesand obesity and for agonizing the β₃ receptor.

[0026] The present invention also relates to methods for treating TypeII diabetes and obesity, as well as a method for agonizing the β₃receptor employing a compound of formula I.

[0027] In addition, the present invention relates to a compound offormula I for use in treating Type II diabetes and obesity as well as acompound of formula I for use in agonizing the β₃ receptor. The presentinvention is further related to the use of a compound of formula I forthe manufacture of a medicament for treating Type II diabetes andobesity as a well as for agonizing the β₃ receptor.

[0028] The present invention is also related to a compound of formulaII:

[0029] which is useful as an intermediate to prepare a compound offormula I.

DETAILED DESCRIPTION

[0030] For the purposes of the present invention, as disclosed andclaimed herein, the following terms are defined below.

[0031] The term “halo” represents fluoro, chloro, bromo, or iodo.

[0032] The terms “C₁-C₆ alkyl” and “C₁-C₄ alkyl” represent a straight,branched or cyclic hydrocarbon moiety having from one to six and one tofour carbon atoms, respectively. C₁-C₄ alkyl groups include methyl,ethyl, n-propyl, isopropyl, cyclopropyl, n-butyl, isobutyl, secbutyl,t-butyl and cyclobutyl. A “C₁-C₄ haloalkyl” group is a C₁-C₄ alkylmoiety substituted with up to six halo atoms, preferably one to threehalo atoms. An example of a haloalkyl group is trifluoromethyl. A “C₁-C₆alkoxy” group is a C₁-C₆ alkyl moiety connected through an oxy linkage.

[0033] The term “divalent hydrocarbon moiety” refers to a straight orbranched chain of carbon atoms that may optionally have one or morepoints of unsaturation. Thus, a hydrocarbon diradical according to thepresent invention includes alkylene, alkenylene and alkylidene moieties.Examples include but are not intended to be limited to methylene,ethylene, propylene, butylene, —CH(CH₃)CH₂——CH(C₂H₅)CH₂—,—CH(CH₃)CH(CH₃)—, —CH₂C(CH₃)₂—, —CH₂CH(CH₃)CH₂—, —C(CH₃)₂CH₂—,—CH═CHCH₂—, —CH═CH—, —C═CCH₂—, and the like.

[0034] The term “optionally substituted” as used herein means anoptional substitution of one to three, preferably one or two groupsindependently selected from oxo, nitro, cyano, phenyl, benzyl, halo,C₁-C₆ alkyl, C₁-C₄ haloalkyl, COR⁵, NR⁶R⁶, NR⁶COR⁵, NR⁶SO₂R⁷, OR⁶,OCOR⁵, OSO₂R⁷, SR⁶, SOR⁷, SO₂R⁷ or SO₂NR⁶R⁶; wherein

[0035] R⁵ is H, C₁-C₆ alkyl, phenyl, benzyl, C₁-C₄ haloalkyl,NR^(6a)R^(6a) or OR^(6a);

[0036] R⁶ and R^(6a) are independently H, C₁-C₆ alkyl or phenyl; or whentwo R⁶ or R^(6a) groups are attached to the same nitrogen atom, said R⁶or R^(6a) groups, together with the nitrogen to which they are attached,may combine to form a piperidine, pyrrolidine, hexamethyleneimine ormorpholine ring; and

[0037] R⁷ is C₁-C₆ alkyl or phenyl.

[0038] The term “heterocyclic ring” represents a stable, saturated,partially unsaturated, fully unsaturated or aromatic ring, said ringhaving from one to four heteroatoms that are independently selected fromthe group consisting of sulfur, oxygen, and nitrogen. The heterocyclemay be attached at any point which affords a stable structure.Representative heterocyclic rings include 1,3-dioxolane,4,5-dihydro-1H-imidazole, 4,5-dihydrooxazole, furan, imidazole,imidazolidine, isothiazole, isoxazole, morpholine, oxadiazole, oxazole,oxazolidinedione, oxazolidone, piperazine, piperidine, pyrazine,pyrazole, pyrazoline, pyridazine, pyridine, pyrimidine, pyrrole,pyrrolidine, tetrazole, thiadiazole, thiazole, thiophene and triazole.Representative “benzofused” heterocyclic rings include benzoxazole,benzimidazole, benzofuran, benzothiophene, benzothiazole, azaindole, andindole. Further specific examples of benzofused and non-benzofusedheterocycles are described below in the Preparations and Examplessections.

[0039] The term “suitable solvent” refers to any solvent, or mixture ofsolvents, inert to the ongoing reaction that sufficiently solubilizesthe reactants to afford a medium within which to effect the desiredreaction.

[0040] The term “patient” includes human and non-human animals such ascompanion animals (dogs and cats and the like) and livestock animals.Livestock animals are animals raised for food production. Ruminants or“cud-chewing” animals such as cows, bulls, heifers, steers, sheep,buffalo, bison, goats and antelopes are examples of livestock. Otherexamples of livestock include pigs and avians (poultry) such aschickens, ducks, turkeys and geese. Yet other examples of livestockinclude fish, shellfish and crustaceans raised in aquaculture. Alsoincluded are exotic animals used in food production such as alligators,water buffalo and ratites (e.g., emu, rheas or ostriches). The preferredpatient of treatment is a human.

[0041] The terms “treating” and “treat”, as used herein, include theirgenerally accepted meanings, i.e., preventing, prohibiting, restraining,alleviating, ameliorating, slowing, stopping, or reversing theprogression or severity of a pathological condition, or sequela thereof,described herein.

[0042] The terms “preventing”, “prevention of”, “prophylaxis”,“prophylactic” and “prevent” are used herein interchangeably and referto reducing the likelihood that the recipient of a compound of formula Iwill incur or develop any of the pathological conditions, or sequelathereof, described herein.

[0043] As used herein, the term “effective amount” means an amount of acompound of formula I that is capable of treating conditions, ordetrimental effects thereof, described herein or that is capable ofagonizing the β₃ receptor.

[0044] The term “selective β₃ receptor agonist” means a compound thatdisplays preferential agonism of the β₃ receptor over agonism of the β₁or β₂ receptor. Thus, β₃ selective compounds behave as agonists for theβ₃ receptor at lower concentrations than that required for similaragonism at the β₁ and β₂ receptors. A β₃ selective compound alsoincludes compounds that behave as agonists for the β₃ receptor and asantagonists for the β₁ and β₂ receptors.

[0045] The term “pharmaceutical” when used herein as an adjective meanssubstantially non-deleterious to the recipient patient.

[0046] The term “formulation”, as in pharmaceutical formulation, isintended to encompass a product comprising the active ingredient(s)(compound of formula I), and the inert ingredient(s) that make up thecarrier, as well as any product which results, directly or indirectly,from combination, complexation or aggregation of any two or more of theingredients, or from dissociation of one or more of the ingredients, orfrom other types of reactions or interactions of one or more of theingredients. Accordingly, the pharmaceutical formulations of the presentinvention encompass any composition made by admixing a compound of thepresent invention and a pharmaceutical carrier.

[0047] The term “unit dosage form” refers to physically discrete unitssuitable as unitary dosages for human subjects and other non-humananimals, each unit containing a predetermined quantity of activematerial calculated to produce the desired therapeutic effect, inassociation with a suitable pharmaceutical carrier.

[0048] Because certain compounds of the invention contain an acidicmoiety (e.g., carboxy), the compound of formula I may exist as apharmaceutical base addition salt thereof. Such salts include thosederived from inorganic bases such as ammonium and alkali and alkalineearth metal hydroxides, carbonates, bicarbonates, and the like, as wellas salts derived from basic organic amines such as aliphatic andaromatic amines, aliphatic diamines, hydroxy alkamines, and the like.

[0049] Because certain compounds of the invention contain a basic moiety(e.g., amino), the compound of formula I can also exist as apharmaceutical acid addition salt. Such salts include the salicylate,sulfate, pyrosulfate, bisulfate, sulfite, bisulfite, phosphate,monohydrogenphosphate, dihydrogenphosphate, metaphosphate,pyrophosphate, chloride, bromide, iodide, acetate, propionate,decanoate, caprylate, acrylate, formate, isobutyrate, heptanoate,propiolate, oxalate, malonate, succinate, suberate, sebacate, fumarate,maleate, 2-butyne-1,4 dioate, 3-hexyne-2, 5-dioate, benzoate,chlorobenzoate, hydroxybenzoate, methoxybenzoate, phthalate,xylenesulfonate, phenylacetate, phenylpropionate, phenylbutyrate,citrate, lactate, hippurate, β-hydroxybutyrate, glycolate, maleate,tartrate, methanesulfonate, propanesulfonate, naphthalene-1-sulfonate,naphthalene-2-sulfonate, mandelate and like salts. Preferred acidaddition salts include the hemifumarate, benzoate, salicylate,R-mandelate, hydrochloride and glycolate salts.

[0050] It is recognized that various stereoisomeric forms of a compoundof formula I exist. The compounds may be prepared as racemates and canbe conveniently used as such. Therefore, the racemates, individualenantiomers, diastereomers, or mixtures thereof form part of the presentinvention. Unless otherwise specified, whenever a compound is describedor referenced in this specification all the racemates, individualenantiomers, diastereomers, or mixtures thereof are included in saidreference or description.

[0051] It is also recognized that various tautomeric forms of a compoundof formula I may exist, and all tautomeric forms are part of the presentinvention. Unless otherwise specified, whenever a compound is describedor referenced in this specification all tautomeric forms, or mixturesthereof, are included in said reference or description.

[0052] Preferred Compounds of the Invention

[0053] Certain compounds of the invention are particularly interestingand are preferred. The following listing sets out several groups ofpreferred compounds. It will be understood that each of the listings maybe combined with other listings to create additional groups of preferredcompounds.

[0054] a) A¹, A² and A³ are carbon;

[0055] b) Het is at the ortho-position relative to X;

[0056] c) Het is optionally substituted one to three times independentlywith halo, hydroxy, oxo, cyano, nitro, phenyl, benzyl, C₁-C₄ alkyl,C₁-C₄ haloalkyl, C₁-C₄ alkoxy, COR⁸, CO₂R⁸, CONR⁸R⁸, NR⁸R⁸, NHCO(C₁-C₄alkyl), NHCO(phenyl), NHCO(benzyl), SR⁸, SO(C₁-C₄ alkyl), SO₂(C₁-C₄alkyl), SO₂(NR⁸R⁸), OCO(C₁-C₄ alkyl), OCO₂R⁸ or OCONR⁸R⁸ where R⁸ isindependently at each occurrence H or C₁-C₄ alkyl;

[0057] d) Het is an optionally substituted 5-membered, non-benzofusedring containing one or two heteroatoms that are independently selectedfrom the group consisting of sulfur, oxygen, and nitrogen;

[0058] e) Het is selected from furan; isothiazole; isoxazole; oxazole;and thiophene; wherein said Het moieties are optionally substituted oncewith fluorine, methyl, cyano, SO₂NH₂ or COCH₃;

[0059] f) Het is selected from thien-2-yl; thien-3-yl; thiazol-2-yl;isoxazol-3-yl; isoxazol-5-yl; and isothiazol-5-yl;

[0060] g) Het is thien-2-yl optionally substituted once with fluorine,methyl, cyano, SO₂NH₂ or COCH₃;

[0061] h) Het is thien-2-yl;

[0062] i) R¹, R^(1a) and R^(1b) are independently H, halo, C₁-C₄ alkyl,C₁-C₄ alkoxy, C₁-C₄ haloalkyl, or SO₂(C₁-C₄ alkyl);

[0063] j) R¹ is H, methyl, ethyl, CF₃, chloro or fluoro;

[0064] k) R¹ is H, methyl, chloro or fluoro;

[0065] l) R¹ is H or fluoro;

[0066] m) R¹ is H;

[0067] n) R^(1a) is H, methyl, ethyl, CF₃, chloro or fluoro;

[0068] o) R^(1a) is H, methyl, chloro or fluoro;

[0069] p) R^(1a) is H;

[0070] q) R^(1b) is H, methyl, ethyl, CF₃, chloro or fluoro;

[0071] r) R^(1b) is H, methyl, chloro or fluoro;

[0072] s) R^(1b) is H;

[0073] t) R² is H or C₁-C₄ alkyl;

[0074] u) R² is H;

[0075] v) R³ and R⁴ are independently H or C₁-C₄ alkyl;

[0076] w) R³ is H or methyl;

[0077] x) R⁴ is H or methyl;

[0078] y) R³ and R⁴ are both methyl;

[0079] z) R⁸ is independently at each occurrence H or C₁-C₄ alkyl;

[0080] aa) X is OCH₂;

[0081] bb) X¹ is a bond, methylene or ethylene;

[0082] cc) X¹ is methylene;

[0083] dd) X² is at the para-position relative to X¹;

[0084] ee) X² is a bond or O;

[0085] ff) X² is O or CH₂;

[0086] gg) X² is O;

[0087] hh) X³ is optionally substituted one to three times independentlywith halo, hydroxy, oxo, cyano, nitro, phenyl, benzyl, C₁-C₄ alkyl,C₁-C₄ haloalkyl, C₁-C₄ alkoxy, COR⁸, CO₂R⁸, CONR⁸R⁸, NR⁸R⁸, NHCO(C₁-C₄alkyl), NHCO(phenyl), NHCO(benzyl), SR⁸, SO(C₁-C₄ alkyl), SO₂(C₁-C₄alkyl), SO₂(NR⁸R⁸), OCO(C₁-C₄ alkyl), OCO₂R⁸ or OCONR⁸R⁸;

[0088] ii) X³ is phenyl, pyridyl, thienyl or furanyl wherein said X³moieties are substituted one to three times with fluoro, chloro, cyano,hydroxy, methyl, ethyl, trifluoromethyl, methoxy, ethoxy, amino, CO₂CH₃,CO₂CH₂CH₃, CONR⁸R⁸, SCH₃, SCH₂CH₃, SOCH₃, SOCH₂CH₃, SO₂CH₃ or SO₂CH₂CH₃;

[0089] jj) X³ is phenyl, pyridyl, thienyl or furanyl wherein said X³moieties are substituted one to three times with fluoro, cyano, hydroxy,methyl, ethyl, methoxy, ethoxy, amino, CO₂CH₃, CO₂CH₂CH₃, CONH₂, SCH₃,SCH₂CH₃, SOCH₃, SOCH₂CH₃, SO₂CH₃ or SO₂CH₂CH₃;

[0090] kk) X³ is phenyl, pyridyl, thienyl or furanyl wherein said X³moieties are substituted one to three times with fluoro, amino, CO₂CH₃,CO₂CH₂CH₃, cyano, CONH₂, SO₂CH₃ or SO₂CH₂CH₃;

[0091] ll) X³ is phenyl, pyridyl or pyridazinyl wherein said X³ moietiesare substituted once or twice with chloro, cyano, CONH₂ or SO₂CH₃;

[0092] mm) X³ is phenyl, pyridyl, thienyl or furanyl wherein said X³moieties are substituted once with cyano or CONH₂;

[0093] nn) X³ is phenyl or pyridyl wherein said X³ moieties aresubstituted once with cyano or CONH₂;

[0094] oo) X³ is pyridyl substituted once with cyano or CONH₂;

[0095] pp) X³ is 5-cyano or 5-carboxamido-pyrid-2-yl;

[0096] qq) X³ is 4-cyano or 4-carboxamido-phenyl;

[0097] rr) X³ is 3-cyano or 3-carboxamido-pyrid-2-yl;

[0098] ss) X³ is 2-cyano or 2-carboxamido-phenyl;

[0099] tt) the compound of formula I is an acid addition salt;

[0100] uu) the compound of formula I is the hydrochloride salt;

[0101] vv) the compound of formula I is the glycolate salt;

[0102] ww) the compound of formula I is the hemi-fumarate salt.

[0103] Synthesis

[0104] The compound of formula I may be prepared as described in thefollowing Schemes and Examples.

[0105] The reaction of Scheme 1 may be carried out under conditionsappreciated in the art for the amination of epoxides. For example, theepoxide of formula II may be combined with an amine of formula III in alower alcohol, dimethylformamide, dimethylsulfoxide, or acetone,preferably ethanol, isopropanol, n-butanol or t-butanal, at roomtemperature to the reflux temperature of the reaction mixture,preferably between 40° C.-90° C. The reaction may also be carried outunder conditions generally described in Atkins, et al., Tet. Let.,27:2451, 1986. These conditions include mixing the reagents in thepresence of trimethylsilyl acetamide in a polar aprotic solvent such asacetonitrile, dimethylformamide, acetone, dimethylsulfoxide, dioxane,diethylene glycol dimethyl ether, tetrahydrofuran, or other polaraprotic solvents in which the reagents are soluble.

[0106] The compound of formula I may also be prepared via a Suzukicoupling as shown in Scheme 2.

[0107] A compound of formula IV may be reacted with a compound offormula III as described above in Scheme 1. The compound of formula V(an aryl halide) may then be reacted with a heteroaryl boronic acid, anaryl boronic ester, or an aryl boronic cyclic ester, preferably an arylboronic acid, under conditions appreciated in the art for the couplingof aromatic halides with aryl boronic acids and their derivatives. Thiscoupling is known in the art generally as a Suzuki coupling. The skilledartisan will recognize that an aryl triflate may also be employed in thepresent Suzuki coupling as an alternative to employing an aryl halide.

[0108] The epoxide starting materials employed in Schemes 1 and 2 may beprepared by techniques recognized and appreciated by one skilled in theart. See, e.g., U.S. Pat. No. 4,663,334; European Patent Application171209; Korn, et al., J. Pharm. Sci., 69(9):1010-13, 1980 and referencescited below in the Preparations section for representative and/oranalogous procedures for preparing the epoxides of formula II and IV. Toillustrate, epoxides of formula II, where X is OCH₂ or SCH₂, may beprepared according to the procedure detailed in Scheme 3 wherein R⁹ isOH or SH and X′ is OCH₂ or SCH₂.

[0109] Equimolar amounts of a compound of formula VI and(2S)-(+)-glycidyl 3-nitrobenzenesulfonate may be dissolved in an inertsolvent such as acetone and treated with a slight excess of a weak base,such as potassium carbonate. The suspension may then be heated at refluxfor 16-20 hours with stirring to provide a compound of formula II(a).Compounds of formula IV, where X is OCH₂ or SCH₂, may be prepared in ananalogous fashion.

[0110] The amino starting materials employed in Schemes 1 and 2 (formulaIII compound) may also be prepared by techniques recognized andappreciated by one skilled in the art. For example, an amine of formulaIII, where X² is

, may be prepared according to the procedure detailed in Scheme 4.

[0111] A compound of formula IX may be prepared by reacting an arylalkylalcohol of formula VII with excess (5 mol/equivalent) formula VIIIcompound by methods well known in the art (see, e.g., Sh. Prikl. Kin.,45:1573-77, 1972). The reaction may also be carried out by mixing thereagents in an aprotic solvent, preferably diglyme, and adding potassiumt-butoxide (0.5 mol/equivalent). The reaction is typically heated atreflux until water present in the reaction mixture is removed (generally2-8 hours). A compound of formula X may then be prepared byhydrogenation of the corresponding compound of formula IX over aprecious metal catalyst. The hydrogenation can be affected at between 20and 60 psi of hydrogen (preferably 50 psi), and with a variety ofsolvents (preferably methanol/acetic acid), temperatures (preferably 50°C.), and catalysts (preferably 5% palladium on carbon wetted withethanol denatured with toluene) well known in the art.

[0112] A skilled artisan will appreciate that a compound of formula Xcould be coupled with a wide variety of halides to yield the claimedethers. The coupling can be carried out according to procedures wellknown in the art and is preferably performed by mixing the startingmaterials in N,N-dimethylacetamide and toluene in the presence ofpotassium carbonate. The reaction is typically then heated to reflux for5 to 24 hours to effect the reaction and to remove water present in thereaction mixture.

[0113] Compounds of formula VI, VII and VIII are either commerciallyavailable, known in the art, or can be prepared by methods known in theart or described herein.

[0114] The following Preparations, Examples and Formulations areprovided so that the invention might be more fully understood. Theyshould not be construed as limiting the invention in any way.

Preparations

[0115] Epoxides of Formula II and IV

[0116] Epoxides 1-21, 23-54 and 56-74 are prepared for use as describedin Scheme 1. Epoxides 22 and 55 are prepared for use as described inScheme 2. These epoxides are pictured in Tables 1 and 2 below. TABLE 1

Het =

[0117] TABLE 2

Y =

Epoxide 1

[0118] A mixture of 2-(1-methylpyrazol-5-yl)phenol (4.

mmol, 810 mg), (2S)-glycidyl 3-nitrobenzenesulfonate (5.58 mmol, 1.45g), potassium carbonate (5.58 mmol, 771 mg) and acetone (40 ml) arerefluxed for 16 hours, cooled to room temperature and the solids removedvia filtration. The filtrate is concentrated and the crude productpurified on silica gel (40% ethyl acetate/hexane) to give 956 mg of thetitle epoxide.

Epoxide 2

[0119] Methyl hydrazine (23.2 mmol, 1.23 ml) is added to a solution of2-(3-hydroxy-2-propen-1-on-1yl)phenol (J. Am. Chem. Soc., 72:3396,1950), 15.4 mmol, 2.54 g) in methanol (7 ml) and the mixture is heatedat 100° C. for one hour. After cooling, the reaction mixture is dilutedwith water (100 ml) and stirred for one hour. The precipitate iscollected via filtration and purified on silica gel (30% ethylacetate/hexane) to give 811 mg of 2-(1-methylpyrazol-3-yl)phenol.

[0120] A mixture of 2-(1-methylpyrazol-3-yl)phenol (4.59 mmol, 800 mg),(2S)-glycidyl 3-nitrobenzenesulfonate (5.51 mmol, 1.42 g), potassiumt-butoxide (5.51 mmol, 515 mg) and tetrahydrofuran (30 ml) are refluxedfor 16 hours, cooled to room temperature and poured into saturatedaqueous ammonium chloride. The aqueous layer is extracted with ethylacetate (3×) and the extracts washed with brine, dried over magnesiumsulfate, and concentrated in vacuo. The crude product is purified onsilica gel (40% ethyl acetate/hexane) to give 785 mg of the titleepoxide.

Epoxide 6

[0121] A mixture of 2-(pyrazol-5-yl)phenol (Catalan, et al., J. Am.Chem. Soc., 114(13):5039-48, 1992, 10 mmol, 1.

g), triethylamine (40.0 mmol, 5.6 ml), and acetonitrile (55 ml) iscooled in an ice bath under N₂ and treated dropwise withchlorotrimethylsilane (12.0 mmol, 1.52 ml). After the addition iscomplete, the cold bath is removed and the reaction mixture stirred atambient temperature for 1 hour. The reaction mixture is then treatedwith trityl chloride (10.0 mmol, 2.78 g) and stirred at ambienttemperature overnight, followed by refluxing for 1 hour. The reactionmixture is concentrated, treated with saturated aqueous sodiumbicarbonate, and extracted with ethyl acetate (3×50 ml). The extractsare dried over magnesium sulfate and concentrated to a viscous oil. Theoil is crystallized from 20% ethyl acetate/hexane to give 1.72 g ofN-trityl-2-(pyrazol-5-yl)phenol.

[0122] A solution of this intermediate phenol (4.27 mmol, 1.72 g) isreacted with (2S)-glycidyl 3-nitrobenzenesulfonate (4.27 mmol, 1.11 g)substantially as decribed for epoxide 2 except that the present reactionis refluxed for 48 hours and the crude product is purified viacrystallization from ethyl acetate to give 860 mg of the title epoxide.

Epoxide 7

[0123] Phenylhydrazine (476 mmol, 51.5 g) and 2-hydroxyacetophenone (476mmol, 64.8 g) are stirred under reflux in dry ethanol (280 ml) for 6hours. After cooling, the crystals are filtered off, washed with coldethanol and dried under vacuum at 50° C. to yield 73 g (68%) of thehydrazone, which is then mixed with nickel chloride (7 g) and heatedunder a nitrogen atmosphere to 240° C. for 3 hours. After cooling, themixture is suspended in dichloromethan

(800 ml), salt is removed by filtration and the filtrate isconcentrated. The resulting crystals are filtered off, washed withdichloromethane (50 ml) and dried in vacuo at 40° C. to give 16.1 g of2-(2-indolyl)phenol (24%). This phenolic product is reacted with(2S)-glycidyl 3-nitrobenzenesulfonate substantially as described forEpoxide 1 to yield the title epoxide.

Epoxide 8

[0124] 2-Hydroxyacetophenone (220 mmol, 30 g) is stirred in a mixture ofdimethylformamide-dimethyl acetal for 5 hours at 70° C., cooled andrecrystallised from diethylether. The intermediate is dissolved in dryethanol (200 ml) and formamidine acetate (0.61 mmol, 63.5 g) is added. Asolution of sodium (0.61 mol, 14 g) in ethanol (450 ml) is added inseveral portions and the mixture is refluxed for 18 hours andevaporated. Recrystallisation from diisopropylether yielded 3.6 g (10%)of 2-(pyrimidin-4-yl)phenol as a solid. This phenolic product is reactedwith (2S)-glycidyl 3-nitrobenzenesulfonate substantially as describedfor Epoxide 1 to yield the title epoxide.

Epoxide 19

[0125] A mixture of 4-chloro-2-hydroxybenzoic acid hydrazide (ChemicalAbstracts, 93:7808, 475 mg, 2.55 mmol) and triethylorthoformate (3.6 ml)is heated at 130° C. for 3.5 hours. After cooling, a precipitate formedand is collected by filtration. The filter cake is recrystallized frommethanol to give 173 mg (35%) of5-chloro-2-(1,3,4-oxadiazol-2-yl)phenol. This phenolic product isreacted with (2S)-glycidyl 3-nitrobenzenesulfonate substantially asdescribed for Epoxide 1 to yield 170 mg (69%) of the titl

epoxide.

Epoxide 20

[0126] A mixture of methyl 3-hydroxybenzoate (5.48 g, 36.0 mmol) and1,2-diaminoethane monotosylate (9.85 g, 42.4 mmol) is heated at 210° C.for 7 hours. After cooling, the mixture is stirred with aqueous 2Nsodium hydroxide and extracted with ethyl acetate. The precipitate whichformed and is present in the aqueous layer is collected by filtrationand dried in vacuo to give 1.3 g (22%) of2-(3-hydroxyphenyl)imidazoline.

[0127] To a solution of 2-(3-hydroxyphenyl)imidazoline (0.895 g, 5.52mmol) in tetrahydrofuran (11 ml) is added water (11 ml), potassiumcarbonate (1.5 g, 10.8 mmol), then di-t-butyl-dicarbonate (1.2 g, 5.5mmol). The resulting mixture is stirred over night before additionaldi-t-butyl-dicarbonate (120 mg) is added and the stirring is continuedfor several hours. The mixture is diluted with water and extracted withethyl acetate. The organic layer is washed with brine, dried over sodiumsulfate, and concentrated under reduced pressure. The residue ispurified via chromatography on silica gel with dichloromethane/ethanol(gradient up to 20:1) to give 615 mg of t-butyl(2-(3-hydroxyphenyl)imidazolin-1-yl)carboxylate (42%). ThisBoc-protected product (610 mg, 2.33 mmol) is reacted with (2S)-glycidyl3-nitrobenzenesulfonate substantially as described for Epoxide 1 toyield 720 mg (97%) of the title epoxide.

Epoxide 22

[0128] A mixture of 2-iodophenol (5.00 g, 22.7 mmol), (2S)-glycidyl3-nitrobenzenesulfonate (5.89 g, 22.7 mmol) and potassium carbonate(3.44 g, 24.9 mmol) in methylethylketone (150 ml) is refluxed for 18hours. After cooling, the salts are removed by filtration. The filtercake is rinsed thoroughly with dichloromethane and the collectedfiltrates are evaporated. The residue is purified via flashchromatography on silica gel using a hexane-hexane/ethyl acetategradient (100 to 90:10).

Epoxide 23

[0129] Sodium (1.21 g, 52.6 mmol) is added to 200 ml methanol to preparea solution of sodium methoxide. After addition of guanidinehydrochloride (12.41 g, 129.9 mmol) and3-(dimethylamino)-1-(2-hydroxyphenyl)-2-propen-1-one (5.0 g, 26.15 mmol;J. Heterocyclic Chem., 14:345, 1977) the mixture is heated at refluxover night. The reaction solvent is removed under reduced pressure, andthe residue treated with water. The resulting precipitate is collectedby filtration and dried in vacuo to give 4.25 g of2-amino-4-(2-hydroxyphenyl)pyrimidine (87%). This pyrimidine precursoris reacted with (2S)-glycidyl 3-nitrobenzenesulfonate substantially asdescribed for Epoxide 1 to give 2.05 g of the title epoxide (37.5%).

Epoxide 24

[0130] A mixture of 3-hydroxyacetophenone (20.0 g, 146.9 mmol) andN,N-dimethylformamide dimethyl acetal (26.26 g, 220.4 mmol) is heatedover night at 100° C. The excess of the acetal is removed under reducedpressure and 3-(dimethylamino)-1-(3-hydroxyphenyl)-2-propen-1-one (10.3.g, 37%) is obtained after chromatography on silica gel withdichloromethane/ethanol 9:1. This intermediate enone is reacted with(2S)-glycidyl 3-nitrobenzenesulfonate substantially as described forEpoxide 1 to give 5.02 g of the title epoxide (78%).

Epoxide 25

[0131] A solution of3-(dimethylamino)-1-(3-hydroxyphenyl)-2-propen-1-one (2.2 g, 11.5 mmol)and hydroxylamine hydrochloride (1.17 g, 16.8 mmol) in 45 mldioxane/water 1:1 is heated for 2 hours at 60° C. The reaction is pouredinto ice-water and the precipitate is collected by filtration, washedwith water, and dried in vacuo to give 1.4 g of 3-(5-isoxazolyl)phenol(75.5%). This phenolic product is reacted with (2S)-glycidyl3-nitrobenzenesulfonate substantially as described for Epoxide 1 to give1.33 g of the title epoxide (70%).

Epoxide 26

[0132] 2-Amino-4-(3-hydroxyphenyl)pyrimidine, prepared substantially asdescribed for 2-amino-4-(2-hydroxyphenyl)pyrimidine, is reacted with(2S)-glycidyl 3-nitrobenzenesulfonate substantially as described forEpoxide 1 to give the title epoxide.

Epoxide 30

[0133] To dioxane (113 ml) is added 2-methoxy-5-fluorophenylboronic acid(4.25 g, 24.9 mmol), 2-bromothiophene (3.65 g, 22.7 mmol, 0.9 eq.) andpotassium carbonate (2M, 37 ml). Palladium (0) tetrakistriphenylphoshine(0.03 eq.) is then added and th

resulting mixture is heated to 85° C. for 3 hours. The reaction iscooled to room temperature and poured into et

l acetate and water. The aqueous layer is extracted twice with ethylacetate. The organic layers are combined, and dried over sodium sulfate,concentrated to a brown oil and the resulting residue is flashchromatographed in 20% toluene/hexanes to afford 11.5 g of2-(thien-2-yl)-4-fluoroanisole (90%).

[0134] The protected product from above (11.0 g, 52.8 mmol) isdemethylated with 110 grams of pyridine hydrochloride neat at 200degrees for 3 hours. The reaction is poured into ice/water and ethylacetate is added. The layers are separated and the organic layer iswashed with water, dried over sodium sulfate and concentrated to a brownsolid. This is then flash chromatographed with 1:3 ethyl acetate/hexanesto afford 7.82 g of 2-(thien-2-yl)-4-fluorophenol (77% yield). Thisphenolic product is reacted with (2S)-glycidyl 3-nitrobenzenesulfonatesubstantially as described for Epoxide 1 to yield the title epoxide.

Epoxide 31

[0135] Epoxide 31 is prepared from 2-methoxy-6-flourophenylboronic acidand 2-bromothiophene by a procedure substantially similar to thatdescribed for Epoxide 30.

Epoxide 33

[0136] A mixture of 2-methoxybenzaldehyde (10.0 g, 73.4 mmol),tosylmethylisocyanide (14.34 g, 73.4 mmol) and potassium carbonate(10.14 g, 73.4 mmol) in 220 ml methanol is heated at reflux for 6 hours.The solvent is removed under reduced pressure and the residue pouredinto ice-water (800 ml). The precipitate is collected by filtration,washed with water, and dried in vacuo to give 9.05 g of 5(2-methoxyphenyl)oxazole (70%).

[0137] Boron tribromide (1M in dichloromethane, 36 ml) is added slowlyto a cold solution (0° C.) of the above oxazole (3.0 g, 17.1 mmol) indichloromethane (215 ml). After stirring over night at room temperature,ice-water (50 ml) is added carefully. The aqueous layer is extractedwith dichloromethane (50 ml), and the combined organic layers are driedover sodium sulfate and concentrated under reduced pressure. Theprecipitate which formed after addition of dichloromethane (70 ml) iscollected by filtration, heated with dichloromethane (15 ml), andfiltered again to give 3.16 g of 2-(5-oxazolyl)phenol. This phenolicproduct is reacted with (2S)-glycidyl 3-nitrobenzenesulfonatesubstantially as described for Epoxide 1 to give 400 mg of the titleepoxide (9.5%).

Epoxide 34

[0138] 2-Methoxyphenylboronic acid (2 eq.) and pyrazole (1 eq.) arecoupled with copper(II) acetate catalysis as described in TetrahedronLett. 39:2941-44, 1998 and the product is demethylated by treatment withboron tribromide in dichloromethane (see, for example, Synth. Commun.27(20):3581-90, 1997) to yield 2-(pyrazol-1-yl)phenol. This phenolicproduct is reacted with (2S)-glycidyl 3-nitrobenzenesulfonatesubstantially as described for Epoxide 1 to give the title epoxide.

Epoxide 35

[0139] 2-(Imidazolidin-2-on-1-yl)anisole (Ger. Offen. 1977, DE 2528079)is demethylated with boron tribromide and the resulting2-(imidazolidin-2-on-1-yl)phenol is reacte

with (2S)-glycidyl 3-nitrobenzenesulfonate substantially

s described for Epoxide 1 to yield the title epoxide.

Epoxide 36

[0140] 2-(Imidazol-1-yl)anisole (L. M. Sitkina, A. M. Simonov, Khim.Geterotsikl. Soedin 1966, 143) is demethylated with boron tribromide andthe resulting 2-(imidazol-1-yl)phenol is reacted with (2S)-glycidyl3-nitrobenzenesulfonate substantially as described for Epoxide 1 to givethe title epoxide.

Epoxide 37

[0141] 3-(Dimethylamino)-1-(4-hydroxyphenyl)-2-propen-1-one is preparedfrom 4-hydroxyacetophenone substantially in the same manner as thatdescribed for 3-(dimethylamino)-1-(3-hydroxyphenyl)-2-propen-1-one(Epoxide 24). 4-(5-Isoxazolyl)phenol is prepared from3-(dimethylamino)-1-(4-hydroxyphenyl)-2-propen-1-one substantially inthe same manner as that described for 3-(5-isoxazolyl)phenol (Epoxide25). This phenolic product is reacted with (2S)-glycidyl3-nitrobenzenesulfonate substantially as described for Epoxide 1 toyield the title epoxide.

Epoxide 45

[0142] 2-(3-Formyl-1-pyrrolyl)phenol (3 g, 16 mmol) and triethylamine(17.6 mmol) are added to a suspension of hydroxylamine hydrochloride(1.22 g, 17.6 mmol) in acetic anhydride (7.7 ml) and the mixture isallowed to stir overnight at ambient temperature. The mixture isrefluxed for 5 hours, concentrated, dissolved in 50 ml ethanol andstirred for 10 min with 50 ml 2 M aqueous sodium hydroxi

e. After neutralisation with aqueous hydrochloric acid, and extractionwith ethylacetate, the organic layer is dried and concentrated. Theresidue is purified by chromatography (toluene/ethanol 9:1) to yield2-(3-cyano-1-pyrrolyl)phenol (2.4 g, 92%). This phenolic product isreacted with (2S)-glycidyl 3-nitrobenzenesulfonate substantially asdescribed for Epoxide 1 to yield the title epoxide.

Epoxide 47

[0143] To 2-(3-formyl-1-pyrrolyl)phenol (2.9 g, 15.5 mmol) in 50 ml drytetrahydrofuran are added sodium cyanoborohydride (1.94 g, 31 mmol) andboron trifluoride diethyletherate (5.7 ml, 47 mmol). The resultingsolution is stirred for 3 hours at ambient temperature. Saturated sodiumbicarbonate (100 ml) is added and the resulting mixture is stirred for 1hour before extraction with t-butylmethylether. The organic layer isdried and concentrated and the residue is purified by chromatography(toluene/ethanol 9:1) to yield 2-(3-methyl-1-pyrrolyl)phenol (300 mg,11%). This phenolic product is reacted with (2S)-glycidyl3-nitrobenzenesulfonate substantially as described for Epoxide 1 toyield the title epoxide.

Epoxide 48

[0144] 2-Bromo-5-fluoro-phenol (0.87 ml, 7.9 mmol) and2-thiopheneboronic acid (2.02 g, 15.8 mmol) are dissolved in 100 mldioxane. The resulting solution is flushed with argon beforetetrakis(triphenylphosphine)palladium (456 mg, 0.395 mmol) and 2 ml ofaqueous 2M sodium carbonate solution (20 mmol) are added. After flushingagain with argon the mixture is refluxed for 15 hours at 100° C. Thesolution is allowed to cool to room temperature and the mixture isfiltered. The filtrate is evaporated and the residue is taken up indichloromethane and extracted with water. The organic layer is driedwith sodium sulfate then concentrated. The residue is purified bychromatography (CH₂Cl₂/EtOH gradient 100:0 to 98:2) to yield 1.13 g of2-(thien-2-yl)-5-fluorophenol (74%).

[0145] 2-(Thien-2-yl)-5-fluorophenol and (2S)-glycidyl3-nitrobenzenesulfonate are reacted as described for the preparation ofEpoxide 1 to give the title epoxide.

Epoxides 49-51

[0146] 2-Bromo-5-fluorophenol is coupled with thiophene-3-boronic acid;2-bromo-4,5-difluorophenol is coupled with thiophene-2-boronic acid; and2-bromo-4,5-difluorophenol is coupled with thiophene-3-boronic acid inSuzuki reactions substantially as described for Epoxide 48, to yield2-(thien-3-yl)-5-fluorophenol; 2-(thien-2-yl)-4,5-difluorophenol; and2-(thien-3-yl)-4,5-difluorophenol, respectively. These phenolic productsare reacted with (2S)-glycidyl 3-nitrobenzenesulfonate substantially asdescribed for Epoxide 1 to yield the title epoxides.

Epoxides 52 and 61

[0147] To a solution of 6-fluorochroman-4-one (21.0 g, 126 mmol) inacetic acid (105 ml) is added bromine (6.5 ml, 126 mmol) at such a rateas to not raise the temperature above 25° C. After the addition iscomplete, the reaction is allowed to stir for 2 hours before pouringinto 1 liter of ice. The resulting mixture is stirred over night. Theprecipitate which formed is filtered and placed in drying oven toproduce 21 g of 3-bromo-6-fluorochroman-4-one.

[0148] The product from (14 g, 57 mmol) above is dissolved intriethylamine (100 ml) and is stirred at ref

ux for 2 hours. The reaction is cooled and concentrated, ta

en up in chloroform, washed with 2N aqueous hydrochloric acid and water.The organic layer is dried over sodium sulfate and concentrated. Theproduct residue is crytallized from hot ethyl acetate.

[0149] The product from above (6-fluorochromen-4-one (5.25 g, 32.0 mmol)and hydroxylamine hydrochloride (4.65 g, 67.2 mmol) are dissolved inethanol (180 ml) and the resulting mixture is heated to reflux. Thereaction is allowed to stir for 18 hours before cooling andconcentrating. The residue is is taken up in toluene and filtered togive 690 mg of 4-fluoro-2-(isoxazol-5-yl)phenol and from the filtrate594 mg of 4-fluoro-2-(isoxazol-3-yl)phenol. These phenolic products areseparately reacted with (2S)-glycidyl 3-nitrobenzenesulfonatesubstantially as described for Epoxide 1 to yield the title epoxides.

Epoxide 53

[0150] 2-Fluoro-6-(thien-3-yl)anisole is prepared from2-fluoro-6-iodoanisole (1.35 g, 5.36 mmol) by Suzuki coupling withthiophene-3-boronic acid according to the general procedure described inRepresentative Procedure 4(b) below; yield: 1.05 g (94%).

[0151] 2-Fluoro-6-(thien-3-yl)phenol is obtained from the anisole (1.0g, 4.8 mmol) with an excess of boron tribromide in dichloromethane bystirring over night. The crude phenol (1.1 g) is used for the next stepwithout further purification.

[0152] Sodium hydride (0.18 g, 4.5 mmol, 60% in oil) is washed severaltimes with hexane under argon and added to a solution of2-fluoro-6-(thien-3-yl)phenol (0.44 g, 2.26 mmol) and (2S)-glycidyl3-nitrobenzenesulfonate (0.587 g 2.26 mmol) in dry tetrahydrofuran (20ml). After stirri

at room temperature over night, the mixture is quenched w

h ice-cold water, diluted with brine, and extracted with eth

l acetate. The organic layer is dried over sodium sulfate, concentratedunder reduced pressure, to give 65 mg (11%) of the title epoxide afterchromatography (silica gel, dichloromethane).

Epoxide 54

[0153] A mixture of 2-bromo-1-(2-benzyloxyphenyl)ethanone (10.0 g, 32.77mmol; prepared according to a procedure from J. Med. Chem., 35:3045,1992) and sodium formate (4.46 g, 65.6 mmol) in dry DMF (100 ml) isstirred at room temperature over night. The mixture is poured into water(400 ml) and extracted with dichloromethane (2×100 ml). The combinedextracts are dried over sodium sulfate and concentrated under reducedpressure.

[0154] The residue is dissolved in acetic acid (100 ml), treated withammonium acetate (12.62 g, 163.7 mmol), and the mixture is heated for 3hours. After cooling, the mixture is diluted with water (400 ml) andextracted with dichloromethane (2×100 ml). The combined organic layersare washed with saturated aqueous sodium bicarbonate solution (2×100ml), dried over sodium sulfate, and concentrated in vacuo.4-(2-Benzyloxyphenyl)oxazole (1.99 g, 24%) is obtained afterchromatography (silica gel, dichloromethane).

[0155] To a solution of the oxazole from above (1.99 g, 7.92 mmol) indichloromethane (20 ml) is added 10% palladium on carbon (1.99 g). Themixture is put under an atmosphere of hydrogen, stirred at roomtemperature over night, then filtered through Celite. The solvent isremoved under reduced pressure to leave 2-(oxazol-4-yl)phenol (1.15 g,90%), which is used for the next step without further purification.

[0156] The title epoxide (1.05 g, 72%) is prepared from the above phenol(1.08 g, 6.7 mmol) and (2S)-glycidyl 3-nitrobenzenesulfonatesubstantially as described for Epoxide 1.

Epoxide 55

[0157] To a solution of 2-fluoro-6-iodoanisole (Justus Liebigs, Ann.Chem., 746:134, 1971; 4.31 g, 17.1 mmol) in dichloromethane (35 ml) isadded a 1M solution of boron tribromide in dichloromethane (18.2 ml).The mixture is kept under argon and stirred for 4 hours at roomtemperature. The mixture is poured into a saturated aqueous sodiumbicarbonate solution and-the aqueous layer is extracted with ethylacetate. The combined organic layers are dried over sodium sulfate andconcentrated under reduced pressure to give 2-fluoro-6-iodophenol (4.2g).

[0158] The title epoxide (4.44 g, 86%) is prepared from the above phenoland (2S)-glycidyl 3-nitrobenzenesulfonate substantiallly as describedfor Epoxide 1 except using butanone as solvent.

Epoxides 56-60

[0159] Epoxides 56, 57, 58, 59 and 60 are prepared from2-methoxy-5-fluorophenylboronic acid and 3-bromothiophene;2-methoxy-6-fluorophenylboronic acid and 5-chloro-2-bromothiophene;2-methoxyphenylboronic acid and 2-bromo-5-fluorothiophene;(3-methoxypyrid-2-yl)boronic acid and 2-bromothiophene; and2-methoxy-6-fluorophenyl and 3-bromothiophene, respectively, by aprocedure substantially similar to that described for Epoxide 30.

Epoxide 62

[0160] A slurry of 2-cyano phenol (25 g, 209.87 mmol), triethylaminehydrochloride (43.3 g, 314.81 mmol), and sodium azide (20.5 g, 314.81mmol) in toluene (200 mL) is heated to the reflux temperature of themixture and then the mixture is allowed to stir at reflux for 15 hours.The mixture is cooled and washed with water (200 mL). The aqueous layeris washed with ether (100 mL), made acidic with concentrated HCl, andthe resulting solid is collected by filtration. The solid is washedtwice with water (200 mL) and dried under vacuum at 100° C. for 15 hoursto give 33.05 g of 2-(tetrazol-3-yl)phenol (97%).

[0161] 2-(Tetrazol-3-yl)phenol (32.8 g, 202.3 mmol) is dissolved indimethylformamide (100 mL) and water (25 mL) and cooled in ice. Sodiumhydroxide (8.49 g, 212.3 mmol) in water (20 mL) is added and thesolution is warmed to ambient temperature. After thirty minutes,iodomethane (31.58 g, 222.5 mmol) is added neat. The solution is stirredfor 15 hours then diluted with ethyl acetate (300 mL) and water (500mL). The aqueous layer is washed three times with ethyl acetate (300 mL)and the organic layers are combined, washed three times with water (1L), once with brine (1.2 L), dried over magnesium sulfate, filtered andconcentrated in vacuo. The solid is purified by flash columnchromatography (80% hexane:20% ethyl acetate gradient to 50% hexane:50%ethyl acetate as an eluent) to give 23.5 g of2-(1-methyltetrazol-3-yl)phenol (66%).

[0162] 2-(1-Methyltetrazol-3-yl)phenol (0.25 g, 1.54 mmol),(2S)-glycidyl 3-nitrobenzenesulfonate (0.42 g, 1.62 mmol), and potassiumcarbonate (0.45 g, 3.23 mmol) is dissolved in methyl ethyl ketone (2mL), the mixture is heated to the reflux temperature of the mixture, andthen is allowed to stir at reflux for 15 hours. The slurry is cooled,filtered and concentrated in vacuo. The solid is purified by flashcolumn chromatography (80% hexane:20% ethyl acetate gradient to 50%hexane:50% ethyl acetate as an eluent) to give 270 mg (75%) of the titleepoxide. FDMS m/e=233 (M⁺+1).

Epoxide 63

[0163] The title epoxide is prepared from 2-hydroxybenzaldehyde andglyoxal by the method described in Eur. J. Med. Chem., 33:181-187, 1998.This phenolic product is reacted with (2S)-glycidyl3-nitrobenzenesulfonate substantially as described for Epoxide 1,however, the title epoxide is used without purification as describedtherein.

Epoxide 64

[0164] 2-Thienyl-1-methoxybenzene (10 g, 53 mmol) is cooled to −78° C.in dry tetrahydrofuran (265 ml) under nitrogen while stirring. n-Butyllithium in hexanes (1.6M, 37 ml, 59 mmol, 1.1 eq.) is added slowly andthe resulting mixture is stirred cold for an hour. Chloromethyl formate(4.1 ml, 53 mmol, 1.0 equivalent) is added and the reaction is stirredcold for another hour. The mixture is allowed to warm to roomtemperature before quenching with saturated bicarbonate solution andethyl acetate. The layers are separated and the organic phase is washedwith brine, dried over sodium sulfate and concentrated. The residue ispurified via flash chromatography in 5% ethyl acetate/hexanes to afford7.9 g of 2-(5-methoxycarbonylthien-2-yl)-1-methoxybenzene (61%).

[0165] 2-(5-Methoxycarbonylthien-2-yl)-1-methoxybenze

is demethylated with boron tribromide to give1-(5-methoxycarbonylthien-2-yl)phenol. This phenolic product i

reacted with (2S)-glycidyl 3-nitrobenzenesulfonate substantially asdescribed for Epoxide 1 to yield the title epoxide.

Epoxide 65

[0166] A solution of 5-bromothiophene-2-carbonitrile (1.25 g, 6.65 mmol)in 50 ml of dioxane is degassed with argon,tetrakis-(triphenylphosphine)-palladium(0) (768 mg, 0.665 mmol) is addedand the mixture is stirred for 5 minutes. 2-Methoxybenzene boronic acid(2.02 g, 13.3 mmol) and aqueous 2 N sodium carbonate (13.3 ml) aresuccessively added and the mixture is stirred for 16 hours at 85° C.Extractive work-up (2×50 ml dichloromethane and 2×30 ml water). Theorganic phase is dried over sodium sulfate, filtrated and evaporated.The residue (4.05 g) is purified via flash column on silica (eluent:100% hexane>hexane/ethyl acetate 96:4 gradient to give 1.37 g of2-(5-cyanothien-2-yl)anisole (96%). M+=215.

[0167] An intimate mixture of 2-(5-cyanothien-2-yl)anisole (1.2 g, 5.9mmol) and pyridinium hydrochloride (13.7 g, 119 mmol) is heated for 1hour to 210° C. under argon. The mixture was cooled to ambienttemperature and a 1:1 mixture of water and ethyl acetate is added tobreak and dissolve the solid cake formed during the reaction. The slurryis then transferred to a separation funnel and dichloromethane is addeduntil the organic phase had a higher density than the water phase(organic phase=lower phase). The organic phase contains the desiredproduct and is separated. The remaining aqueous phase is additionallyextracted twice with dichloromethane and the collected organic phasesare dried over sodium sulfate and evaporated. The residue is purifiedvia flash column on silica (eluen

100% hexane>hexane/ethyl acetate 8:2 gradient) to give 973 mg of2-(5-cyanothien-2-yl)phenol (87%). M+=201.

[0168] To a solution of 2-(5-cyanothien-2-yl)phenol (970 mg, 4.819 mmol)in 20 ml of dry 2-butanone is added (2S)-glycidyl3-nitrobenzenesulfonate (1.25 g, 4.82 mmol) and potassium carbonate (732mg, 5.30 mmol) successively. After stirring for 48 hours at 75° C., themixture is diluted with ethyl acetate and extracted with 2N aqueoussodium hydroxide (2×30 ml) and water (1×30 ml). (M+=257).

Epoxides 66-70

[0169] Epoxides 66-70 are prepared by a procedure substantially similarto that described for Epoxide 65. The starting halogeno thiophenes usedto prepare Epoxides 65-70 are known from the literature, see e.g., J.Mater. Chem., 5(4), 653-61, 1995; J. Chem. Soc., Perkin Trans. 2,5:625-30, 1982; Chem. Scr., 5(5), 217-26, 1974; Bull. Soc. Chim. Fr.,11:4115-20, 1967; Bull. Soc. Chim. Fr., 11:4121-6, 1967; Bull. Inst.Chem. Res., 52(3):561-5, 1974; J. Med. Chem., 43(16):3168-3185, 2000;Bioorg. Med. Chem. Lett., 10(5):415-418, 2000; and JP 08311060.

Epoxide 73

[0170] A 25 ml 1-propanol solution of 2-methoxyphenyl boronic acid (1.2g, 7.5 mmol) and 5-bromothien-2-ylsulfonamide (1.2 g, 5 mmol) is stirredunder N₂ at room temperature. Palladium(II) acetate (56 mg, 0.25 mmol),triphenylphosphine (200 mg, 0.75 mmol), 2M aqueous Na₂CO₃ (3 ml, 6mmol), and 7 ml H₂O are added and the resulting mixture is refluxed(˜88° C.) for 1 hour. The reaction is cooled, diluted with ethylacetate, washed with brine, and the brine back extracted with ethylacetate. The extract are combined, washed with aqueous NaHCO₃, brine,dried (Na₂SO₄), filtered, and the filtrate is concentrated. The residueis purified by chromatography (SiO₂, ethyl acetate/hexane gradient) togive 943 mg (70%) of 5-(2-methoxyphenyl)thiophene-2-sulfonamide.

[0171] A 70 ml CH₂Cl₂ suspension of5-(2-methoxyphenyl)thiophene-2-sulfonamide (1.0 g, 3.7 mmol) is stirredunder N₂ at −75° C. as boron tribromide (1.1 ml, 12 mmol) is syringedinto the reaction mixture. The amber solution is stirred for 30 minutesat −75° C., then at 0° C. for 2-3 hours. The reaction is quenched withice, extracted with CH₂Cl₂. The extracts are washed with brine, dried(Na₂SO₄), filtered, and the filtrate is concentrated. The residue ispurified by chromatography (SiO₂, ethyl acetate/hexane gradient) to give720 mg of 5-(2-hydroxyphenyl)thiophene-2-sulfonamide (76%).

[0172] 5-(2-Hydroxyphenyl)thiophene-2-sulfonic acid amide (1.8 g, 7.1mmol), K₂CO₃ (1.1 g, 8.5 mmol), and (2S)-glycidyl3-nitrobenzenesulfonate (2.1 g, 7.8 mmol) are reacted as described forthe preparation of Epoxide 1 to give 1.5 g of the title epoxide (70%).

Epoxide 74

[0173] (2-Methoxyphenyl)acetaldehyde is prepared by oxidation of2-(2-methoxyphenyl)ethanol according to the procedure disclosed in J.Org. Chem., 49:1720, 1999. A mixture of (2-methoxyphenyl)acetaldehyde(3.8 g, 25.3 mmol) and dimethylformamide dimethyl acetal (4.52 g, 37.9mmol) is stirred at room temperature for 1 hour. Excess of the acetal isremoved under reduced pressure to leave 4.68 g of3-dimethylamino-2-(2-methoxyphenyl)propenal (90%).

[0174] A solution of 3-dimethylamino-2-(2-methoxyphenyl)propenal (4.68g, 22.8 mmol) and hydrazine hydrate (6.7 ml) in ethanol (100 ml) isheated at reflux

or 30 minutes. The solvent is removed in vacuo and the residue ischromatographed (silica gel, dichloromethane/ethanol 95:5) to give 2.69g of 4-(2-methoxyphenyl)pyrazole (68%).

[0175] To a solution of 4-(2-methoxyphenyl)pyrazole (300 mg, 1.72 mmol)in dichloromethane (13 ml) is added a 1M solution of boron tribromide(3.8 ml) in dichloromethane. The mixture is stirred at room temperatureover night then concentrated under reduced pressure. The residue ischromatographed (silica gel, dichloromethane/ethanol 9:1) to give 270 mgof 2-(pyrazol-4-yl)phenol (98%).

[0176] 2-(Pyrazol-4-yl)phenol and (2S)-glycidyl 3-nitrobenzenesulfonateare reacted as described for the preparation of Epoxide 1 to give 180 mgof the title epoxide (50%).

Epoxides 3-5, 9-18, 21, 27-29, 32, 38-41, 43, 46, 71 and 72

[0177] 2-(Thien-2-yl)phenol (J. Heterocycl. Chem., 22(6):1667-9, 1985);2-(thiazol-2-yl)phenol (Arnold, et al., WO 94/22846);2-(5-isoxazolyl)phenol; 2-(pyrrolidin-2-on-1-yl)phenol (Tetrahedron,26(17):4207-4212, 1970); 2-morpholinophenol; 2-piperidinophenol;1-(2-hydroxyphenyl)piperazine; 2-(2-hydroxyphenyl)benzoxazole;2-(2-hydroxyphenyl)benzothiazole; 2-(4,4-dimethyl-2-oxazolin-2-yl)phenol(Bioorg. Med. Chem. Lett., 6(18):2173-76, 1996);2-(1-pyrrolidino)phenol; 2-(pyrrol-1-yl)phenol (J. Het. Chem.,8:283-287, 1971); 2-(1,3,4-oxadiazol-2-yl)phenol (WO 94/22846);2-(isoxazol-3-yl)phenol (J. Het. Chem., 8:283-287, 1971);2-(isothiazol-5-yl)phenol (J. Chem. Res. (S), 349, 1988; J. Chem. Res.(S), 163, 1992); 2-(1,3,4-thiadiazol-2-yl)phenol (WO 94/22846);2-(1,2,3-thiadiazol-4-yl)phenol; 2-(oxazol-2-yl)phenol (WO 94/22846);4-(2-hydroxyphenyl)-2(5H)-furanone (Ger. Offen. DE2829414);4-4-fluoro-2-hydroxyphenyl)-2(5H) -furanone (Ger. Offen. DE2829414);2-(furan-3-yl)phenol (Ger. Offen. DE2914166); 2-thiazol-4-yl-phenol (WO94/22846); 2-(thiazol-4-yl)phenol (WO 94/22846);2-(4,5-dimethylimidazol-2-yl)phenol (Eur. J. Med. Chem., 33:181-187,1998, using 4,5-dimethylimidazole instead of imidazole);2-(3-formylpyrrol-1-yl)phenol (J. Het. Chem., 283-287, 1971 using2,5-dimethoxy-3-formyl-tetrahydrofuran instead of2,5-dimethoxy-tetrahydrofuran); 2-(3-methylisoxazol-5-yl)phenol (J. Org.Chem., 49:4419, 1984); and 2-(4-methylisoxazol-5-yl)phenol (Pol. J.Chem., 56:501, 1982) are reacted with (2S)-glycidyl3-nitrobenzenesulfonate substantially as described for Epoxide 1 toyield the title epoxides.

[0178] Amines of Formula III

[0179] Amines 1-49 are prepared for use as described in Schemes 1 and 2.These amines are pictured in Tables 3-5 below. TABLE 3

X³ =

[0180] TABLE 4

X³ =

[0181] TABLE 5

X³ =

[0182] Amines 1 and 10 may be prepared according to procedures detailedin U.S. Ser. No. 09/068,192, the teachings of which are hereinincorporated by reference. Amines 11, 26 and 33 may be prepared by aprocedure substantially similar to that described for Amine 1. Amines 2,3, 8, and 9 may be prepared according to procedures detailed in U.S.Pat. No. 5,977,154, the teachings of which are herein incorporated byreference. Amines 27, 29 and 40 may be prepared by a proceduresubstantially similar to that described for Amine 9.

Amine 4

[0183] 4-(2-Amino-2-methylpropyl)phenol (50.8 g, 225 mmol),2-chloro-3-cyanopyridine (30.8 g, 222 mmol), potassium carbonate (77.7g, 562 mmol, powdered), N,N-dimethylacetamide (609 ml), and isooctane(122 ml) are combined and heated to reflux. The water formed during thereaction is removed azeotropically via a Dean-Stark trap. After about1-2 hours the reaction is complete. The slurry is cooled to 30° C. andfiltered. The filter cake is washed with N,N-dimethylacetamide (250 ml)and the combined organic fractions are concentrated by rotaryevaporation at 80° C. The resulting dark green oil is dissolved indichloromethane (580 ml), and washed with water (160 ml). The phases areseparated and the organic phase washed with water (250 ml). Water (1 L)is added to the organic phase and the pH adjusted to 1 with 12N aqueoushydrochloric acid (about 25 ml). The phases are separated and the acidicaqueous layer is washed with dichloromethane (250 ml). Dichloromethane(1 L) is added to the acidic aqueous phase and the pH is adjusted to12-13 with 5N aqueous sodium hydroxide. The phases are separated and theorganic phase is dried over sodium sulfate. After filtration thesolution is concentrated to give 53 g of the title amine (88%).

Amine 6

[0184] 4-(2-Amino-2-methylpropyl)phenol (55.18 g, 244.9 mmol) is addedto 5.05N KOH (97.2 mmol). The mixture is warmed to 50° C. to give ahomogeneous yellow solution. Chlorobenzene (1104 ml) andN,N-dimethylacetamide (10.7 g, 122 mmol) is added and the mixture isheated to reflux (about 100° C.). The water is removed azeotropicallyvia a Dean-Stark trap. At about 125° C. a solid began to form. When thepot temperature reached 132° C. the water has been removed and thereaction mixture is a thick but stirable slurry (mechanical stirringrequired). The Dean-Stark trap is removed and an additional 100 ml ofchlorobenzene is removed and discarded. Dry chlorobenzene (50 ml) isadded to the slurry, followed by ethyl 2-chloronicotinate (50.0 g, 269mmol) in chlorobenzene (50 ml). The slurry is heated at reflux until thereaction is complete (about 24 hours). After cooling to roomtemperature, water (385 ml) and 1N NaOH (25 ml, 0.1 equiv) is added tothe mixture and the phases are separated. The organic phase is washedwith water (285 ml) and the solution is concentrated to a net weight of700 g (89%).

Amine 7

[0185] 4-(2-Amino-2-methylpropyl)phenol (3.00 g, 18.2 mmol), methyl6-chloronicotinate (3.27 g, 19.1 mmol), powdered potasssium carbonate(3.76 g, 27.2 mmol, 300 mesh), N,N-dimethylacetamide (60 ml), andtoluene (15 ml) are combined and heated to reflux. The water formedduring the reaction is removed azeotropically via a Dean-Stark trap.After about 2 hours, the internal temperature reached 154° C. and thereaction is complete. The slurry is cooled to 30° C. and filtered. Thefilter cake is washed with N,N-dimethylacetamide and the combinedorganic fractions concentrated by rotary evaporation at 75° C. Theresulting oil is dissolved in ethyl acetate (50 ml), and washed withwater (30 ml). The phases are separated and the aqueous phase isextracted with ethyl acetate (20 ml) after some saturated aqueous sodiumchloride solution (10 ml) is added to facilitate phase separation. Thecombined organic fractions are washed with water (2×30 ml) and saturatedaqueous sodium chloride (30 ml) and then dried over sodium sulfate.After filtration the solution is concentrated to give 4.60 g (80%) ofthe title amine.

Amine 12

[0186] 2-Cyano-3-chloropyridine (Bremner, et al., Syn. Comm., 27:1535,1997; Kaneda, et al., Chem. Pharm. Bull., 33:565, 1985) is coupled to4-(2-amino-2-methylpropyl)phenol to prepare the title amine by aprocedure substantially similar to that described above for Amine 4.

Amine 24

[0187] Potassium tert-butoxide (58.6 ml, 58.6 mmol, 1M intetrahydrofuran) is added to a solution of 3,4-dichlorothiophenol (10.0g, 55.8 mmol) in tetrahydrofuran (300 ml) at 0° C. and the solutionstirred for 30 minutes. Methyl iodide (8.32 g, 58.6 mmol) is addeddropwise and the resulting slurry is stirred for 16 hours. The solventsare removed in vacuo and the residue is dissolved in 150 ml each ofmethyl-t-butyl ether and 1M NaHSO₄. The phases are separated and theorganic layer is washed with 150 ml each of water and saturated aqueoussodium chloride. The organic layer is dried over sodium sulfate,filtered and concentrated in vacuo to give 9.67 g of 3,4-dichlorophenylmethylsulfide (90%).

[0188] The sulfide from above is converted to the corresponding sulfoneas described below for Amine 38. The 3,4 dichloromethyl sulfone iscoupled to 4-(2-amino-2-methylpropyl)phenol to prepare the title amineby a procedure substantially similar to that described above for Amine4.

Amine 31

[0189] To a 1 gallon autoclave is added 2,5-dichloropyridine (123 g, 830mmol), palladium II acetate (5.6 g, 24.9 mmol),1,3-bis(diphenylphosphine)propane (20.5 g, 49.8 mmol),1,1,1,3,3,3,-hexamethyldisilazane (700 ml), acetonitrile (1180 ml) anddimethylformamide (295 ml). The autoclave is pressurized to 70 psi withcarbon monoxide and heated to 80° C. for 16 hours. The reaction mixtureis filtered and washed with acetonitrile. The mixture is concentrated invacuo to 590 g and 1L of water is added. The resulting slurry is cooledto 0° C. and filtered to give 102.6 g (79%) of2-carboxamido-5-chloropyridine which is used without furtherpurification.

[0190] 2-Carboxamido-5-chloropyridine is coupled to4-(2-amino-2-methylpropyl)phenol to prepare the title Amine by aprocedure substantially similar to that described above for Amine 4.

Amine 36

[0191] Oxalyl chloride (18.1 ml, 207 mmol) is added slowly todimethylformamide cooled to −25° C. The resulting mixture is cooled to−45° C. and 2-carboxamido-5-chloropyridine (25 g, 160 mmol) is addedportionwise. The reaction stirred for 30 minutes and pyridine (14.2 ml,176 mmol) is added. The reaction stirred for 5 hours, 20 minutes and ispoured into 1.5 L of water and 1 L of ethyl acetate is added. The phasesare separated and the aqueous layer is extracted with 100 ml of ethylacetate. The combined organics are washed with water (850 ml and 350ml), saturated aqueous sodium chloride (100 ml), dried over sodiumsulfate, filtered and concentrated in vacuo to give 19.95 g (92%) of2-cyano-5-chloropyridine which is used without further purification.

[0192] 2-Cyano-5-chloropyridine is coupled to4-(2-amino-2-methylpropyl)phenol to prepare the title amine by aprocedure substantially similar to that described above for Amine 4.

Amine 38

[0193] To a solution of n-butyl lithium (0.544 mol) in tetrahydrofuran(700 ml) at −78° C. is added a solution of 3,4-difluorobromobenzene (100g, 0.518 mol) in 200 ml of tetrahydrofuran. After 10 minutes, a solutionof dimethyl disulfide in 100 ml of tetrahydrofuran is added and theresulting reaction mixture is warmed to ambient temperature over 60minutes. The reaction is concentrated in vacuo and the resulting oil ispartitioned between 750 ml methyl-t-butyl ether and 300 ml water. Thephases are separated and the organic layer is washed with 300 ml ofsaturated aqueous sodium chloride, dried over magnesium sulfate,filtered, and concentrated in vacuo. The resulting oil is purified byvacuum distillation to provide 43.08 g of 3,4-difluorophenylmethylsulfide.

[0194] Metachloroperbenzoic acid (60.4 mmol) is added portionwise to asolution of the sulfide (43 g, 26.8 mmol) in 1L of dichloromethane at 0°C. After 15 minutes, the reaction mixture is warmed to ambienttemperature and stirred for 1.25 hours. The solids are removed byfiltration and the resulting solution washed with 750 ml of 1M sodiumbisulfite, 2L sodium bicarbonate, 1L water, and 750 ml saturated aqueoussodium chloride. The organic layer is dried over magnesium sulfate,filtered and concentrated in vacuo to give 45.17 g (88%) of the titleamine.

Amine 41

[0195] The acetic acid salt of 4-(2-amino-2-methylpropyl)phenol (15 g,66.5 mmol) is dissolved in 90 ml of hot water. 5N aqueous sodiumhydroxide (13.98 ml, 0.0699 mol) is added and the resulting mixture isallowed to stir for one hour upon which a precipitate formed. Thereaction is then placed in the refrigerator to allow more precipitation.The precipitate is filtered to afford 6.91 g of4-(2-amino-2-methylpropyl)phenol free base.

[0196] 4-(2-Amino-2-methylpropyl)phenol free base (6.91 g, 41.8 mmol) isdissolved in 100 ml of anhydrous tetrahydrofuran and the solution ispurged with nitrogen. Di-t-butyl-dicarbonate (10.56 ml, 46 mmol) isadded and the resulting solution is allowed to stir overnight. Thereaction is concentrated, the residue dissolved in ethyl acetate, andthen washed with water. The organic layer is dried over sodium sulfate,filtered and concentrated to a clear oil. The oil is taken up inanhydrous tetrahydrofuran and diisopropylethylamine (7.94 ml, 46 mmol)is added followed by trifluoromethanesulfonic anhydride (7.67 ml, 45mmol). The reaction is allowed to stir for 3 hours, quenched with water,extracted with ethyl acetate, dried over sodium sulfate and concentratedto a clear solid.

[0197] A portion of the above solid (2.7 g, 6.8 mmol) is mixed with3-cyanophenyl boronic acid (1.0 g, 6.8 mmol), aqueous potassiumcarbonate (2M, 7.1 ml, 14.3 mmol), lithium chloride (288 mg, 6.8 mmol)and 60 ml of tetrahydrofuran. The reaction is fitted with a condenserand purged with nitrogen before palladium(0) tetrakistriphenylphoshineis added (37.9 mg, 0.34 mmol). The reaction flask is covered withaluminum foil and the solution is brought to reflux. After 16 hours, thereaction is poured into a separatory funnel. Ethyl acetate (100 ml) isadded and the organic layer is washed with water, 1N aqueous HCl, water,1N aqueous sodium hydroxide and again with water. The organic layer isdried over sodium sulfate and concentrated to a brown solid. The crudeproduct is purified on a silica flash column eluting with 20% ethylacetate/80% hexanes to give 900 mg of the amine protected title amine.

[0198] The protected amine from above (1.025 g, 2.9 mmol) is placed in aflask and stirred with trifluoroacetic acid (neat). After 10 minutes,the solution is concentrated and taken up in 10 ml of methanol. Thissolution is then placed on a 10 g SCX column and washed with methanol(2×10 ml). The product is eluted with methanolic ammonia (2M) to give735 mg of the title amine.

Amine 43

[0199] Carbonyldiimidazole (43.0 g, 265 mmol) is added in one portion toa solution of 2-chloro-5-carboxythiophene (39.2 g, 241 mmol) in 400 mlof tetrahydrofuran. The resulting mixture is allowed to stir for 60minutes before aqueous ammonium hydroxide (28%, 125 ml) is added in oneportion. After stirring for 90 minutes, the mixture is concentrated invacuo and the residue is dissolved in ethyl acetate (750 ml). Thisorganic solution is washed with aqueous sodium hydroxide (1N, 100 ml)and then four times with aqueous hydrochloric acid (1N, 100 ml). Theorganic layer is dried over sodium sulfate, filtered, and concentratedin vacuo, and dried overnight at 40° C. in vacuo to give 22.6 g of2-chloro-5-carboxamidothiophene.

[0200] Oxalyl chloride (8.9 ml, 102 mmol) is added dropwise to a coldsolution (−40° C.) of 2-chloro-5-carboxamidothiophene (15 g, 92.8 mmol)in dimethylformamide (150 ml). After the addition is complete, thereaction is allowed to stir for 2 hours before it is diluted with ethylacetate (500 ml). The resulting mixture is washed four times with water(25 ml), dried over sodium sulfate, and concentrated in vacuo to give12.3 g of 2-chloro-5-cyanothiophene.

[0201] 2-Chloro-5-cyanothiophene (3.8 g, 26.6 mmol) and4-(2-amino-2-methylpropyl)phenol (4.0 g, 17.8 mmol) are dissolved indimethylsulfoxide (15 ml). Sodium hydride (60% dispersion in oil, 1.5 g)is added in portions over 2 hours. The first addition (about half of thetotal) is done at room temperature. The reaction is heated to 50° C. andthe remaining sodium hydride is added in portions. After the additionsare complete, the reaction mixture is heated to 90° C. and is allowed tostir for 44 hours. After allowing the reaction mixture to cool, it isdiluted with dichloromethane (45 ml) and water (90 ml). The layers areseparated and the organic layer is washed with water (15 ml). Water (77ml) is added to the organic layer and the pH of the aqueous phase isadjusted to 1 with concentrated hydrochloric acid (1.9 ml). The aqueouslayer is washed with dichloromethane (14 ml) and then the pH is adjustedto 13 with aqueous sodium hydroxide (5N, 14 ml). The aqueous layer isextracted three times with dichloromethane (90 ml, 2×45 ml). Theextracts are combined, dried over sodium sulfate, and concentrated invacuo to give 3.5 g of the title amine.

Amine 48

[0202] 2-Methyl-hydroxy-phenol (15.0 g, 0.12 mol), 2-nitro propane (60.8ml, 676 mmol)., potassium t-butoxide (6.77 g, 60 mmol) and diglyme (150ml) are mixed together in a reaction vessel and said vessel is fittedwith a Dean-Stark water trap. The reaction is heated to 134° C. untilwater and solvent began to collect in the trap. The reaction is slowlyheated to 149° C. and then is allowed to cool back down to 130° C. atwhich point the reaction is stirred for 3 hours. Reaction is cooled toroom temperature and water (20 ml) is added. After concentrating toabout half the volume, water (100 ml) is added and the mixture isextracted with ethyl acetate (2×100 ml). The organic layer is thenwashed with 1N aqueous hydrochloric acid and water, dried over sodiumsulfate and concentrated to a brown oil. A mixture of ethyl acetate andhexanes, (300 ml, 1:4 ethyl acetate/hexanes) is added and product istriturated.

[0203] The product from above (7.0 g) is taken up in methanol and aceticacid and 5% palladium on carbon is added. Hydrogen gas is injected intothe reaction vessel up to 50 p.s.i. The mixture is then heated to 50° C.and shaken for 16 hours. The catalyst is filtered and the reaction isconcentrated. Ethyl acetate (400 ml) is added and product is filtered togive 7.55 g of 2-(2-amino-2-methylpropyl)phenol acetic acid salt.2-(2-Amino-2-methylpropyl)phenol acetic acid salt is converted to itsfree base form, the free base is reacted with di-t-butyl-dicarbonate,and the protected amine is reacted with 4-cyanophenyl boronic acid toprepare the title amine substantially as described above for Amine 41.

Amines 5, 13-23, 25, 28, 30, 32, 34, 35, 37, 39, 42, 44-47 and 49

[0204] Amines 5, 13-23, 25, 28, 30, 32, 34, 35, 37 and 39 are preparedby procedures substantially similar to that described for Amine 4.Amines 42 and 47 are prepared by procedures substantially similar tothat described for Amine 41. Amines 44-46 are prepared by proceduressubstantially similar to that described for Amine 43. Amine 49 isprepared by procedures substantially similar to that described for Amine48.

[0205] Aryl Halides of Formula V

[0206] Aryl halides 1-14 are prepared for use as described in Scheme 2.These aryl halides are pictured below in Tables 6 and 7. TABLE 6

X³ =

[0207] TABLE 7

X³ =

[0208] Representative Procedure 1: Preparation of Aryl Halides

[0209] (2S)-1-(2-iodophenyloxy)-2,3-epoxypropane (Epoxide 22, 8 mmol) or(2S)-1-(2-iodo-6-fluorophenyloxy)-2,3-epoxypropane (Epoxide 55) isreacted with an equimolar amount of an amine of formula III (Amines 2-5,9, 10, 12, 31, 36 or 40) in 100 ml of refluxing dry ethanol overnight.After evaporation of the solvent the residue is purified via flashchromatography on silica gel using adichloromethane-dichloromethane/ethanolic ammonia gradient (100 to95:5).

[0210] Boronic Acids

[0211] The following boronic acids or cyclic esters are obtained fromcommercial sources for use as described in Scheme 2. TABLE 8

EXAMPLES

[0212] Representative Procedure 2: Amination of Epoxide

[0213] A vial is charged with a solution of single amine of formula III(0.2M in ethanol or t-butanol, 90 micromolar) and a solution of a singleepoxide of formula II (0.2M in dimethylsulfoxide, 80 micromolar). Thevial is sealed and heated to 80° C. for 24-48 hours. The solution iscooled to room temperature, diluted with methanol, and passed over acation exchange column, eluting the basic material with 1N methanolicammonia.

[0214] Representative Procedure 3: Amination of Epoxide

[0215] A stirred mixture of an epoxide of formula II (1 equivalent) andan amine of formula III (1-2 equivalents) in ethanol, methanol,n-butanol or t-butanol is heated at 70-80° C. for 2-72 hours. Thesolvent is evaporated to dryness to give a crude oil that is optionallydiluted with methanol or ethanol and passed over a cation exchangecolumn (eluting the free base product with 1N methanolic ammonia) beforefurther purification.

[0216] The final products prepared via Representative Procedure 2 or 3may be further purified by flash or radial chromatography. Typicalchromatography conditions include: a) using a variable mixture of 25:5:1chloroform/methanol/ammonium hydroxide and 9:1 chloroform/methanol; b) avariable mixture of 90:10:1 CH₂Cl₂/ethanolic NH₃ gradient; c)dichloromethane/6-12% methanol, 0.15-0.35M ammonia in dichloromethanegradient; d) methylene chloride with a step gradient to 2-8% methanol;e) chloroform/2.0M ammonia in methanol, from 0-10% to 6-20% gradientelution or f) isocratic 6-8% 2M ammonia in methanol: 92-94%dichloromethane.

[0217] Alternatively, the final products may be purified on C18 bondedsilica gel using either mass guided or UV guided reverse phase liquidchromatography (acetonitrile/water with 0.01% hydrochloric acid or 0.1%trifluoroacetic acid). When purification of a compound of the presentinvention results in production of a free base, the free base thusprepared may be salified, e.g., by dissolution of the free base inCH₂Cl₂ or diethylether, adding 1M ethanolic HCl or a solution of HCl indiethylether, and evaporating the volatiles, or as described in moredetail below.

[0218] For example, a hydrochloride salt may be prepared by dissolvingthe free base in dichloromethane, diethylether, or a mixture of ethylacetate and methanol and adding 1M ethanolic HCl, a solution of HCl indiethylether, or 0.5M ammonium chloride. The resulting mixture isallowed to stir for a short time, e.g., for five minutes, beforeevaporating the volatiles and optionally triturating in diethyl ether togive the hydrochloride salt.

[0219] The oxalate salts may be prepared by dissolving the free base ina small amount of ethyl acetate, optionally adding methanol forsolubitity. The resulting solution is treated with 1 equivalent of a0.5M solution of oxalic acid in ethyl acetate. The reaction mixture iseither concentrated in vacuo or centrifuged, separated, and the solidsare dried, to give the oxalate salt.

[0220] To prepare a succinate salt, the free base may be dissolved in asmall amount of ethyl acetate or methanol and then treated with 1equivalent of succinic acid in methanol. The resulting slurry isdissolved in the minimum amount of methanol then concentrated in vacuoto give the succinate salt.

[0221] For products synthesized from Epoxide 6, the c

de products are treated with 1N HCl/dioxane for 2 hours at roomtemperature and concentrated before purifying on C18 bonde

silica gel as described above to give a compound of the formula:

[0222] For products synthesized from Epoxide 20, the title compounds areprepared by removal of the Boc-protecting group from the imidazolinering by stirring a solution of the crude protected product indichloromethane/2N HCl 10:1.

[0223] For products synthesized from Epoxide 24, the intermediateN,N-dimethyl

s are treated with hydrazine hydrate in ethanol to give a compound ofthe formula:

[0224] The table below sets out representative combinations of Aminesand Epoxides that are reacted as described above in RepresentativeProcedure 2 or 3. Preparation of desired product is confirmed via massspectral analysis (MSA). Emax±Standard Error Mean (SEM) data, discussedin the “Demonstration of Function” section below, is also included forsaid compounds where available. The Emax values represent the average ofat least 3 runs except as otherwise indicated. TABLE 9 E.g. EpoxideAmine MSA Isolated Form Emax (%) ± SEM 1 3 1 475.2 Trifluoro Acetate58.1 ± 2.6 2 5 1 460.2 Trifluoro Acetate 43.6 ± 9.7 3 1 2 498.3 FreeBase <10 4 2 4 498.3 Free Base 55.0 ± 1.3 5 3 2 500.3 Free Base 66.1 ±4.8 6 4 2 501.3 Free Base 58.7 ± 1.8 7 5 2 485.0 Free Base 48.8 ± 2.5 86 2 484.1 Free Base 33.7 ± n = 1 9 7 2 533.4 Free Base 23.7 ± 10.0 10 82 496.6 Free Base 35.1 ± 0.9 11 9 2 501.4 Free Base 18.0 ± 6.5 12 21 2485.2 Hydrochloride 64.8 ± 6.3 13 33 2 485.3 Hydrochloride 54.8 ± 1.7 141 3 516.3 Free Base 16.9 ± n = 1 15 2 5 516.3 Free Base 70.9 ± 3.0 16 33 518.3 Free Base 67.6 ± 4.7 17 4 3 519.3 Free Base 62.9 ± 2.2 18 5 3503.0 Free Base 49.1 ± 2.9 19 6 3 502.1 Free Base 31.3 ± n = 1 20 7 3551.5 Free Base 30.4 ± 2.5 21 7 5 551.4 Free Base 48.0 ± 2.0 22 9 3519.3 Free Base 22.0 ± 5.3 23 10 3 521.4 Di-Hydrochloride 29.9 ± 3.2 2411 3 519.5 Di-Hydrochloride 17.3 ± 3.2 25 12 3 520.4 Tri-Hydrochloride13.7 ± 3.5 26 13 3 553.3 Free Base 41.4 ± 6.6 27 14 3 569.3 Free Base20.8 ± 8.5 28 15 3 533.3 Free Base 83.4 ± 7.2 29 17 3 501.3Hydrochloride 48.4 ± 5.9 30 18 3 504.5 Free Base 51.7 ± 2.7 31 19 3538.3 Free Base 12.1 ± n = 1 32 21 3 503.3 Hydrochloride 54.2 ± 5.0 3323 3 529.3 Free Base 26.2 ± 4.3 34 24 3 502.4 Free Base <10 35 25 3503.3 Free Base 28.9 ± n = 1 36 37 3 503.3 Free Base 17.5 ± n = 1 37 5 3489.2 Trifluoro Acetate 41.5 ± 0.5 38 26 3 529.3 Free Base 20.5 ± n = 139 27 3 519.2 Oxalate 67.1 ± 0.7 40 27 3 500.3 Trifluoro Acetate 79.5 ±6.7 41 38 3 518.3 Hydrochloride 33.5 ± 4.2 42 28 3 520.2 Oxalate 43.3 ±2.7 43 40 3 502.4 Hydrochloride 61.9 ± 2.5 44 29 3 520.2 Oxalate 22.1 ±3.3 45 32 3 503.3 Free Base 66.5 ± 3.9 46 33 3 503.3 Hydrochloride 64.7± 1.3 47 34 3 502.4 Hydrochloride 35.5 ± 5.5 48 1 4 498.3 Free Base 14.4± n = 1 49 2 2 498.3 Free Base 59.1 ± n = 1 50 3 4 500.3 Free Base 78.9± 2.5 51 3 4 499.9 Hydrochloride 74.1 ± 3.3 52 4 4 501.3 Free Base 70.1± 3.3 53 5 4 485.0 Free Base 74.5 ± 12.5 54 5 4 484.9 Hydrochloride 66.8± 6.8 55 6 4 484.1 Free Base 37.5 ± n = 1 56 7 4 533.3 Free Base 30.1 ±2.1 57 8 4 496.4 Free Base 41.8 ± 5.6 58 9 4 501.3 Free Base 21.0 ± 3.459 20 3 504.3 Free Base <10 60 21 4 485.2 Hydrochloride 70.8 ± 3.1 61 234 511.4 Free Base 32.8 ± 4.3 62 37 4 485.3 Trifluoro Acetate 24.7 ± 5.263 30 4 518.2 Oxalate 52.6 ± 2.5 64 31 4 518.2 Trifluoro Acetate 30.5 ±6.8 65 33 4 485.3 Hydrochloride 55.9 ± 5.8 66 1 5 516.3 Free Base 26.6 ±n = 1 67 2 3 516.3 Free Base 77.4 ± n = 1 68 3 5 518.3 Free Base 83.7 ±3.0 69 3 5 517.9 Hydrochloride 80.7 ± 4.4 70 4 5 519.3 Free Base 73.8 ±6.0 71 4 5 518.9 Hydrochloride 65.6 ± 1.3 72 5 5 503.0 Free Base 67.6 ±7.1 73 5 5 502.9 Hydrochloride 69.5 ± 0.1 74 6 5 502.1 Free Base 36.8 ±n = 1 75 8 3 514.5 Free Base 40.3 ± 3.7 76 8 5 514.3 Free Base 48.8 ±5.5 77 9 5 519.3 Free Base 22.4 ± 4.6 78 10 5 521.4 Di-Hydrochloride30.3 ± 5.1 79 11 5 519.3 Di-Hydrochloride 21.3 ± 3.3 80 12 5 520.4Tri-Hydrochloride 12.3 ± 0.2 81 13 5 553.3 Free Base 60.4 ± 5.1 82 14 5569.2 Free Base 45.9 ± 10.7 83 15 5 533.3 Hydrochloride 83.5 ± 4.4 84 165 505.3 Free Base 72.1 ± 6.2 85 17 5 501.2 Hydrochloride 69.2 ± 12.1 8618 5 504.3 Free Base 64.6 ± 3.3 87 19 5 538.1 Free Base 14.2 ± n = 1 8820 5 504.3 Free Base <10 89 21 5 503.3 Hydrochloride 71.8 ± 2.5 90 23 5529.5 Free Base 31.5 ± 2.8 91 26 5 529.3 Free Base 24.9 ± 9.3 92 24 5502.4 Free Base 14.4 ± n = 1 93 25 5 503.3 Free Base <10 94 37 5 503.3Free Base <10 95 39 5 536.3 Hydrochloride 13.9 ± 0.1 96 27 5 519.2Oxalate 78.1 ± 6.6 97 28 5 520.2 Oxalate 52.4 ± 0.8 98 29 5 520.2Oxalate 39.2 ± 4.0 99 30 5 536.2 Oxalate 59.1 ± 0.6 100 31 5 536.2Trifluoro Acetate 31.4 ± 5.0 101 33 5 503.3 Hydrochloride 67.4 ± 4.0 10234 5 502.4 Hydrochloride 46.1 ± 4.5 103 35 5 520.5 Free Base 21.1 ± 0.1104 36 5 502.4 Hydrochloride 36.0 ± 5.0 105 1 6 545.4 Free Base <10 1062 6 545.3 Free Base 53.2 ± 2.4 107 3 6 547.3 Free Base 84.3 ± 5.3 108 36 547.2 Trifluoro Acetate 87.1 ± 11.9 109 4 6 548.3 Free Base 61.4 ± 4.4110 5 6 532.0 Free Base 60.3 ± 3.9 111 6 6 531.1 Free Base 23.6 ± n = 1112 5 6 532.2 Trifluoro Acetate 56.9 ± 8.6 113 1 7 531.3 Free Base 20.7± n = 1 114 2 7 531.3 Free Base 56.6 ± n = 1 115 3 7 533.3 Free Base61.9 ± 7.0 116 4 7 534.3 Free Base 58.2 ± 7.2 117 5 7 518.0 Free Base32.2 ± 6.5 118 6 7 517.1 Free Base 29.5 ± n = 1 119 3 8 499.2 TrifluoroAcetate 55.2 ± 3.6 120 4 8 500.2 Trifluoro Acetate 35.8 ± 4.6 121 5 8484.3 Trifluoro Acetate 38.9 ± 7.1 122 27 8 505.3 Trifluoro Acetate 61.9± 5.3 123 3 9 516.2 Trifluoro Acetate 73.6 ± 8.2 124 4 9 518.2 TrifluoroAcetate 46.7 ± 3.6 125 5 9 502.2 Trifluoro Acetate 40.3 ± 7.9 126 27 9518.2 Trifluoro Acetate 62.2 ± 1.3 127 1 10 550.3 Free Base <10 128 2 10550.3 Free Base 40.6 ± n = 1 129 3 10 552.2 Trifluoro Acetate 53.2 ± 4.8130 4 10 553.3 Free Base 49.5 ± 3.4 131 4 10 552.9 Trifluoro Acetate43.5 ± 1.4 132 5 10 537.0 Free Base 34.6 ± 7.8 133 6 10 536.1 Free Base21.4 ± n = 1 134 21 10 537.4 Hydrochloride 47.7 ± 6.5 135 5 10 537.2Trifluoro Acetate 35.2 ± 4.3 136 39 10 570.2 Hydrochloride <10 137 1 11564.3 Free Base <10 138 2 11 564.3 Free Base 41.7 ± n = 1 139 3 11 566.3Free Base 62.2 ± 7.4 140 4 11 567.3 Free Base 48.9 ± 2.5 141 5 11 551.0Free Base 48.3 ± 9.9 142 6 11 550.1 Free Base 20.2 ± n = 1 143 3 12500.2 Trifluoro Acetate 67.2 ± 4.8 144 4 12 501.2 Trifluoro Acetate 55.9± 1.1 145 4 36 501.2 Trifluoro Acetate 44.6 ± 6.2 146 5 12 484.2Trifluoro Acetate 58.7 ± 2.9 147 27 12 501.2 Trifluoro Acetate 58.9 ±3.6 148 30 12 536.2 Trifluoro Acetate 51.6 ± 9.7 149 31 12 518.2Trifluoro Acetate 26.9 ± 4.0 150 3 13 476.2 Trifluoro Acetate 69.8 ± 6.0151 4 13 477.2 Trifluoro Acetate 73.1 ± 3.8 152 5 13 461.2 TrifluoroAcetate 45.3 ± 4.2 153 3 14 476.2 Trifluoro Acetate 66.8 ± 5.5 154 4 14477.3 Trifluoro Acetate 61.1 ± 7.7 155 5 14 461.2 Trifluoro Acetate 46.6± 4.2 156 3 15 577.1 Trifluoro Acetate 84.9 ± 0.2 157 4 15 578.1Trifluoro Acetate 73.3 ± 6.6 158 5 15 562.1 Trifluoro Acetate 73.0 ± 3.0159 3 16 577.2 Trifluoro Acetate 76.9 ± 7.4 160 5 16 562.2 TrifluoroAcetate 56.3 ± 1.4 161 3 17 533.2 Trifluoro Acetate 52.5 ± 4.7 162 4 17428.2 Trifluoro Acetate 36.2 ± 2.6 163 5 17 518.2 Trifluoro Acetate 44.6± 4.3 164 3 18 551.2 Trifluoro Acetate 67.3 ± 3.5 165 4 18 552.2Trifluoro Acetate 49.7 ± 3.9 166 5 18 536.2 Trifluoro Acetate 58.3 ± 9.5167 3 19 509.2 Trifluoro Acetate 57.3 ± 3.5 168 4 19 510.2 TrifluoroAcetate 56.1 ± 4.5 169 5 19 494.2 Trifluoro Acetate 43.3 ± 6.8 170 3 20576.2 Trifluoro Acetate 55.0 ± 4.8 171 4 20 * Trifluoro Acetate 47.9 ±6.5 172 5 20 561.2 Trifluoro Acetate 40.4 ± 8.8 173 3 21 543.2 TrifluoroAcetate 87.9 ± 4.5 174 5 21 528.2 Trifluoro Acetate 59.3 ± 3.2 175 3 22509.2 Trifluoro Acetate 67.4 ± 3.9 176 4 22 510.2 Trifluoro Acetate 57.0± 7.6 177 5 22 494.2 Trifluoro Acetate 46.0 ± 1.7 178 3 23 509.2Trifluoro Acetate 64.4 ± 5.2 179 4 23 510.2 Trifluoro Acetate 62.2 ± 8.6180 5 23 494.2 Trifluoro Acetate 52.4 ± 6.9 181 3 24 586.2 TrifluoroAcetate 66.2 ± 1.6 182 4 24 587.1 Trifluoro Acetate 57.6 ± 7.1 183 5 24571.2 Trifluoro Acetate 53.7 ± 4.3 184 3 25 564.2 Trifluoro Acetate 64.1± 3.2 185 4 25 565.2 Trifluoro Acetate 45.1 ± 2.6 186 5 25 549.2Trifluoro Acetate 41.1 ± 8.2 187 3 26 517.2 Trifluoro Acetate 45.1 ± 1.5188 4 26 518.2 Trifluoro Acetate 38.3 ± 5.7 189 5 26 502.2 TrifluoroAcetate 35.1 ± 5.2 190 3 27 535.2 Trifluoro Acetate 54.5 ± 3.3 191 4 27536.2 Trifluoro Acetate 49.5 ± 1.5 192 5 27 520.2 Trifluoro Acetate 40.3± 6.9 193 3 28 543.2 Trifluoro Acetate 73.5 ± 3.2 194 4 28 544.2Trifluoro Acetate 56.6 ± 4.2 195 5 28 528.2 Trifluoro Acetate 48.1 ± 3.8196 3 29 518.2 Trifluoro Acetate 74.4 ± 3.3 197 4 29 519.2 TrifluoroAcetate 67.7 ± 2.7 198 5 29 503.2 Trifluoro Acetate 48.1 ± 6.5 199 27 29519.3 Trifluoro Acetate 83.0 ± 4.0 200 30 29 518.2 Trifluoro Acetate59.5 ± 3.7 201 31 29 517.2 Trifluoro Acetate 26.8 ± 4.2 202 3 30 475.2Trifluoro Acetate 59.1 ± 6.0 203 4 30 476.2 Trifluoro Acetate 57.8 ± 3.1204 3 37 580.2 Trifluoro Acetate 67.6 ± 4.0 205 3 31 518.2 TrifluoroAcetate 70.3 ± 0.3 206 4 31 519.2 Trifluoro Acetate 64.2 ± 8.1 207 27 31519.2 Trifluoro Acetate 70.5 ± 4.9 208 3 32 510.2 Trifluoro Acetate 92.4± 7.3 209 4 32 511.2 Trifluoro Acetate 88.3 ± 8.0 210 5 32 * TrifluoroAcetate 89.1 ± 2.7 211 27 32 511.2 Trifluoro Acetate 88.5 ± 9.3 212 5 33484.7 Trifluoro Acetate 68.9 ± 3.1 213 27 33 500.2 Trifluoro Acetate63.0 ± 3.2 214 30 33 517.2 Trifluoro Acetate 42.4 ± 9.4 215 31 33 535.2Trifluoro Acetate 28.1 ± 4.5 216 3 34 533.2 Trifluoro Acetate 85.4 ± 4.9217 5 34 518.2 Trifluoro Acetate 76.2 ± 8.3 218 3 35 551.2 TrifluoroAcetate 76.5 ± 1.7 219 5 35 536.2 Trifluoro Acetate 50.4 ± 6.3 220 3 36500.3 Trifluoro Acetate 56.0 ± 2.9 221 5 36 484.2 Trifluoro Acetate 40.8± 8.3 222 4 37 581.2 Trifluoro Acetate 59.0 ± 10.0 223 3 38 570.2Trifluoro Acetate 63.7 ± 3.1 224 4 38 571.2 Trifluoro Acetate 37.0 ± 0.3225 3 39 571.2 Trifluoro Acetate 59.5 ± 4.3 226 4 39 572.2 TrifluoroAcetate 37.8 ± 9.2 227 30 40 535.2 Trifluoro Acetate 51.3 ± 10.8 228 3140 535.2 Trifluoro Acetate 28.9 ± 3.4 229 5 41 468.2 Oxalate 34.7 ± 4.3230 5 42 468.2 Oxalate 30.8 ± 6.0 231 3 43 505.2 Trifluoro Acetate 65.9± 4.2 232 5 43 490.2 Trifluoro Acetate 37.4 ± 2.8 233 3 44 523.2Trifluoro Acetate 71.0 ± 4.7 234 5 44 508.2 Trifluoro Acetate 44.0 ± 4.4235 3 45 * Trifluoro Acetate 60.5 ± 5.6 236 5 45 474.2 Trifluoro Acetate36.8 ± 1.6 237 3 46 507.2 Trifluoro Acetate 57.7 ± 1.1 238 5 46 492.2Trifluoro Acetate 47.6 ± 2.4 239 41 4 501.2 Hydrochloride 49.8 ± 4.5 24041 5 519.2 Hydrochloride 65.7 ± 3.8 241 41 12 501.2 Hydrochloride 47.0 ±2.5 242 41 29 519.2 Hydrochloride 55.9 ± 4.0 243 41 33 500.2Hydrochloride 47.9 ± 3.5 244 41 40 518.2 Hydrochloride 66.6 ± 5.7 245 4134 534.2 Hydrochloride 56.1 ± 2.9 246 41 35 552.2 Hydrochloride 52.1 ±2.4 247 41 2 501.2 Hydrochloride 45.4 ± 3.4 248 41 3 519.2 Hydrochloride47.5 ± 4.8 249 41 10 553.2 Hydrochloride 35.9 ± 2.9 250 41 38 571.2Hydrochloride 31.6 ± 3.1 251 41 39 572.2 Hydrochloride 33.4 ± 5.7 252 4127 536.2 Hydrochloride 38.4 ± 3.8 253 41 18 552.2 Hydrochloride 37.6 ±2.7 254 41 16 578.2 Hydrochloride 50.5 ± 0.8 255 41 22 510.2Hydrochloride 41.4 ± 3.9 256 41 14 477.3 Hydrochloride 50.6 ± 1.8 257 4113 477.2 Hydrochloride 49.9 ± 3.4 258 41 43 506.2 Hydrochloride 48.4 ±5.6 259 41 44 524.2 Hydrochloride 54.1 ± 3.9 260 41 45 490.2Hydrochloride 38.2 ± 2.0 261 41 46 508.2 Hydrochloride 52.3 ± 6.6 262 435 530.2 Dihydrochloride 63.6 ± 4.3 263 17 4 486.6 Hydrochloride 64.3 ±9.6 264 17 2 486.6 Hydrochloride 39.4 ± 10.1 265 17 10 535.7Hydrochloride 42.7 ± 9.4 266 17 31 501.6 Hydrochloride 36.7 ± 6.8 267 1736 486.6 Hydrochloride 37.1 ± 2.5 268 17 12 483.6 Hydrochloride 54.6 ±8.2 269 17 9 500.6 Hydrochloride 41.3 ± 4.2 270 17 40 500.6Hydrochloride 56.4 ± 8.3 271 45 5 526.6 Hydrochloride 39.0 ± 0.6 272 453 526.6 Hydrochloride 35.7 ± 2.8 273 46 5 529.6 Free Base 40.3 ± 0.5 27446 3 529.6 Free Base 38.8 ± 1.4 275 47 5 514.6 Hydrochloride 47.0 ± 1.4276 47 3 514.6 Hydrochloride 53.8 ± 2.0 277 48 3 536.6 Hydrochloride42.3 ± 11.1 278 48 5 536.6 Hydrochloride 27.5 ± 2.7 279 49 3 536.6Hydrochloride 17.0 ± 2.7 280 49 5 536.6 Hydrochloride 38.4 ± 5.1 281 503 554.6 Hydrochloride 15.6 ± 0.1 282 50 5 554.6 Hydrochloride 17.4 ± 2.1283 51 3 554.6 Hydrochloride <10 284 51 5 554.6 Hydrochloride 10.8 ± 0.3285 3 2 500.2 Oxalate 24.6 ± 3.8 286 3 33 499.1 Trifluoroacetate 72.1 ±4.5 287 5 30 * Trifluoroacetate 39.9 ± 4.9 288 5 37 * Trifluoroacetate52.9 ± 7.4 289 5 47 468.2 Oxalate 37.4 ± 7.2 290 5 48 468.2Hydrochloride 22.7 ± 1.7 291 5 49 468.2 Hydrochloride 18.4 ± n = 1 29252 4 503.3 Trifluoroacetate 43.5 ± 9.8 293 52 5 521.3 Trifluoroacetate50.1 ± 5.6 294 52 12 503.3 Trifluoroacetate 43.9 ± 4.4 295 52 33 502.3Trifluoroacetate 39.7 ± 8.7 296 52 40 520.2 Trifluoroacetate 47.9 ± 4.4297 21 12 485.3 Hydrochloride 74.5 ± 6.7 298 21 31 503.4 Hydrochloride54.5 ± 0.8 299 21 9 502.4 Hydrochloride 45.9 ± 3.9 300 21 36 485.3Hydrochloride 52.2 ± 5.9 301 21 40 502.4 Hydrochloride 69.2 ± 1.2 302 393 536.3 Hydrochloride 12.8 ± n = 1 303 40 5 502.4 Hydrochloride 67.9 ±6.1 304 40 10 536.3 Hydrochloride 44.8 ± 4.9 305 40 2 484.3Hydrochloride 68.8 ± 6.5 306 40 4 484.4 Hydrochloride 82.4 ± 4.0 307 4012 484.3 Hydrochloride 74.4 ± 1.8 308 32 5 503.3 Hydrochloride 71.2 ±5.8 309 54 3 503.3 Hydrochloride 67.1 ± 1.2 310 54 5 503.3 Hydrochloride72.7 ± 3.4 311 54 2 485.2 Trifluoroacetate 51.5 ± 1.7 312 54 4 485.4Trifluoroacetate 59.8 ± 3.1 313 53 5 535.9 Trifluoroacetate 29.3 ± 4.1314 60 12 518.3 Trifluoroacetate 42.0 ± 2.0 315 60 29 535.9Trifluoroacetate 39.9 ± 2.5 316 60 40 535.3 Trifluoroacetate 58.8 ± 3.1317 56 40 535.2 Trifluoroacetate 56.4 ± 5.0 318 56 33 517.2Trifluoroacetate 41.8 ± 3.8 319 56 12 518.2 Trifluoroacetate 49.9 ± 3.9320 56 5 536.2 Trifluoroacetate 51.4 ± 2.1 321 56 4 518.2Trifluoroacetate 42.5 ± 2.3 322 57 4 552.1 Trifluoroacetate 27.6 ± 3.9323 57 5 570.1 Trifluoroacetate 33.8 ± 3.8 324 57 12 570.2Trifluoroacetate 38.5 ± 6.7 325 57 33 569.2 Trifluoroacetate 31.6 ± 7.8326 57 40 569.2 Trifluoroacetate 30.4 ± 2.1 327 4 46 508.2Trifluoroacetate 56.7 ± 2.1 328 4 43 506.1 Trifluoroacetate 57.4 ± 6.5329 4 44 524.2 Trifluoroacetate 60.2 ± 3.0 330 4 45 490.2Trifluoroacetate 55.9 ± 2.8 331 58 4 518.2 Hydrochloride 72.9 ± 2.0 33258 5 537.2 Hydrochloride 80.6 ± 2.4 333 58 12 518.2 Hydrochloride 72.4 ±3.0 334 58 33 517.0 Hydrochloride 77.8 ± 3.0 335 59 4 501.2Hydrochloride 66.5 ± 1.8 336 59 5 519.2 Hydrochloride 68.8 ± 2.4 337 5912 501.2 Hydrochloride 52.8 ± 3.7 338 59 33 500.2 Hydrochloride 65.5 ±3.9 339 63 5 502.3 Hydrochloride 40.5 ± 1.2 340 43 3 530.3Di-Hydrochloride 28.1 ± 2.3 341 63 3 502.3 Free Base 46.2 ± 6.3 342 3 34533.2 Hydrochloride Not Tested 343 5 34 518.2 Hydrochloride Not Tested344 27 5 519.2 Hydrochloride Not Tested 345 64 5 576.1 Oxalate 72.1 ±4.2 346 64 29 576.1 Oxalate 57.3 ± 6.3 347 65 5 543.3 Hydrochloride 84.8± 3.4 348 66 5 532.3 Trifluoro Acetate 72.6 ± 5.5 349 67 5 543.3Trifluoro Acetate 57.4 ± 3.3 350 68 5 532.3 Trifluoro Acetate 45.8 ± 1.9351 69 5 543.3 Trifluoro Acetate 64.3 ± 1.3 352 70 5 532.0 TrifluoroAcetate 68.5 ± 2.5 353 73 5 597.3 Hydrochloride 96.5 ± 9.7 354 74 5502.4 Hydrochloride 73.5 ± 2.5 355 32 31 503.3 Trifluoroacetate 66.6 ±3.3 356 54 9 502.4 Trifluoroacetate 65.2 ± 1.9 357 54 31 503.2Trifluoroacetate 65.4 ± 2.6 358 54 40 502.1 Trifluoroacetate 68.4 ± 1.5359 72 3 517.6 Trifluoroacetate 31.2 ± 4.4 360 72 5 517.3Trifluoroacetate 49.9 ± 3.5 361 32 9 502.4 Trifluoroacetate 70.1 ± 2.2362 54 12 485.3 Trifluoroacetate 56.2 ± 2.9 363 54 36 485.3Trifluoroacetate 50.1 ± 4.9 364 32 36 485.0 Trifluoroacetate 69.2 ± 2.5365 32 40 502.0 Trifluoroacetate 80.2 ± 5.6 366 71 3 517.2Trifluoroacetate 47.9 ± 3.5 367 71 5 517.2 Trifluoroacetate 69.5 ± 4.6368 71 2 499.3 Trifluoroacetate 48.4 ± 2.5 369 71 4 499.4Trifluoroacetate 59.3 ± 3.1

[0225] Representative Procedure 4: Suzuki Coupling

[0226] Procedure 4(a)

[0227] A compound of formula V (6.4 mmol) is dissolved in 50 ml of drydioxane and thoroughly flushed with argon. Palladium(0)tetrakis(triphenylphosphine) (750 mg, 0.64 mmol) is added under argonand stirred at ambient temperature until the mixture becomes homogenous.The clear solution is divided into aliquots of 2 ml, and each testingtube is charged with 2 equivalents of an aryl boronic acid of formula IVand 500 μl of 2M aqueous sodium carbonate under argon. The testing tubesare sealed and heated in a microwave oven (MLS ETHOS 1600) for 35minutes and 100° C. at 1000 W. After complete conversion the samples arediluted with 2 ml of water and extracted with 3 ml of dichloromethane.Extraction is repeated with 2 ml of dichloromethane. The organicsolutions are collected and dried over sodium sulfate. The organicfiltrate is treated with pre-treated Amberlyst 15 (3 to 4 g each).(Prior to use Amberlyst 15 is prewashed with dichloromethane, ethanolthen dichloromethane until the filtrate is colorless). The suspensionsare shaken for 30 minutes on an orbital shaker and filtered. TheAmberlyst is repeatedly rinsed with dichloromethane/ethanol 1:1 (4×3 ml)and then repeatedly treated with dichloromethane/ethanolic ammonia 1:1.Finally the resin is treated with ethanolic ammonia overnight. Thealkaline filtrates are collected and evaporated.

[0228] Procedure 4(b)

[0229] A mixture of an aryl halide of formula V (1.2 mmol), a boronicacid of formula IV (2.4 mmol), palladium(0) tetrakis(triphenylphosphine)(0.06 mmol), and 2M aqueous sodium carbonate (1.5 ml) in dioxane (20 ml)is heated over night at 100° C. in a sealed tube. The mixture is pouredinto water and extracted two times with ethyl acetate. The combinedorganic layers are washed with brine, dried over sodium sulfate, andconcentrated under reduced pressure.

[0230] The final products prepared via Suzuki coupling may be purifiedby normal phase chromatography (silica gel, dichloromethane/ethanolicammonia) providing the free bases or by reverse phase chromatography(acetonitrile/0.1% trifluoroacetic acid or 0.01% HCl in water) providingthe trifluoro acetate or hydrochloride salts. The final productsexisting as salts may also be prepared in a separate salification stepby dissolution of the free base in ethanol or dichloromethane andtreatment of the solution with acid, e.g., 1N ethanolic HCl. Removal ofall volatiles under reduced pressure, affords the desired salt.

[0231] The table below sets out representative combinations of arylhalides and boronic acids that are reacted as described above.Preparation of desired product is confirmed via mass spectral analysis(MSA). Emax±Standard Error Mean (SEM) data, discussed in the“Demonstration of Function” section below, is also included for saidcompounds where available. The Emax values represent the average of atleast 3 runs except as otherwise indicated. TABLE 10 Aryl Boronic E.g.Halide Acid MSA Salt Form Emax (%) ± SEM 370 2 1 552.3 Free Base 40.3 ±2.8 371 3 1 534.2 Free Base 38.9 ± 3.9 372 4 1 552.3 Free Base 56.3 ±4.8 373 1 2 495.7 Free Base 29.0 ± 6.8 374 2 2 513.5 Free Base 49.3 ±0.3 375 3 2 495.8 Free Base 35.1 ± 7.3 376 4 2 513.5 Free Base 48.2 ±6.7 377 5 2 547.2 Di-Hydrochloride 33.0 ± 4.2 378 1 3 500.5 Free Base60.2 ± 3.2 379 2 3 518.5 Free Base 37.7 ± 1.6 380 3 3 500.3 Free Base57.4 ± 4.1 381 4 3 518.3 Trifluoro Acetate 58.5 ± 6.9 382 5 3 552.3Hydrochloride 32.3 ± 1.9 383 5 10 552.1 Hydrochloride 52.1 ± 5.4 384 1 4550.6 Free Base 45.4 ± 5.6 385 2 4 568.3 Free Base 43.1 ± 4.3 386 3 4550.7 Free Base 46.9 ± 6.7 387 4 4 568.2 Trifluoro Acetate 78.7 ± 14.9388 1 5 495.8 Free Base <10 389 2 5 513.5 Free Base 20.3 ± 2.0 390 3 5495.8 Free Base 14.4 ± 1.7 391 4 5 513.5 Free Base 22.5 ± 1.5 392 5 5547.4 Di-Hydrochloride 17.6 ± 0.4 393 5 6 586.0 Hydrochloride 50.0 ± 3.6394 5 7 594.3 Hydrochloride 76.9 ± 5.0 395 5 8 536.3 Hydrochloride 46.6± 5.9 396 5 9 566.1 Hydrochloride 50.5 ± 1.9 397 6 10 518.4Hydrochloride 29.9 ± 4.4 398 6 3 518.4 Hydrochloride 22.1 ± 1.7 399 7 10536.3 Hydrochloride 37.3 ± 3.7 400 7 3 536.3 Hydrochloride 26.0 ± 3.5401 8 10 518.4 Hydrochloride 46.3 ± 6.8 402 8 3 518.4 Trifluoroacetate31.1 ± 3.3 403 9 10 536.3 Hydrochloride 57.9 ± 11.2 404 9 3 536.3Hydrochloride 40.4 ± 7.8 405 1 9 514.3 Hydrochloride 64.4 ± 7.1 406 1 6534.0 Trifluoroacetate 55.8 ± 7.1 407 1 7 542.2 Hydrochloride 79.7 ± 7.6408 1 8 484.3 Hydrochloride 74.0 ± 6.5 409 2 9 532.2 Hydrochloride 71.3± 3.9 410 2 6 552.3 Hydrochloride 76.0 ± 5.0 411 2 7 560.3Trifluoroacetate 78.2 ± 9.9 412 2 8 502.4 Hydrochloride 74.4 ± 7.0 413 39 514.3 Hydrochloride 66.9 ± 9.2 414 3 6 534.3 Trifluoroacetate 65.7 ±11.4 415 3 7 542.3 Trifluoroacetate 80.6 ± 5.7 416 3 8 484.3Hydrochloride 68.9 ± 6.7 417 4 9 532.2 Hydrochloride 79.3 ± 2.4 418 4 6552.4 Hydrochloride 74.4 ± 6.5 419 4 7 560.2 Trifluoroacetate 87.5 ± 1.8420 4 8 502.4 Hydrochloride 78.9 ± 2.3 421 10 3 517.3 Hydrochloride 53.4± 6.9 422 10 9 531.3 Hydrochloride 60.1 ± 8.2 423 10 6 551.4Hydrochloride 63.1 ± 4.7 424 10 7 559.1 Hydrochloride 71.2 ± 7.9 425 108 501.3 Hydrochloride 67.1 ± 3.0 426 11 3 517.3 Hydrochloride 61.0 ± 7.1427 11 9 531.3 Hydrochloride 72.4 ± 6.9 428 11 6 551.3 Hydrochloride75.5 ± 6.9 429 11 7 559.3 Trifluoroacetate 84.7 ± 12.3 430 11 8 501.3Hydrochloride 77.4 ± 9.0 431 12 3 500.3 Hydrochloride 50.3 ± 7.8 432 129 514.3 Hydrochloride 60.7 ± 8.4 433 12 6 534.2 Hydrochloride 56.5 ±11.0 434 12 7 542.3 Trifluoroacetate 73.1 ± 5.1 435 12 8 484.3Hydrochloride 61.4 ± 6.1 436 13 3 518.4 Hydrochloride 57.5 ± 12.0 437 139 532.2 Hydrochloride 72.0 ± 10.5 438 13 6 552.3 Hydrochloride 64.3 ±12.4 439 13 7 560.1 Trifluoroacetate 75.0 ± 9.6 440 13 8 502.4Hydrochloride 73.4 ± 4.4 441 14 3 500.3 Hydrochloride 64.2 ± 7.0 442 149 514.3 Hydrochloride 61.5 ± 3.0 443 14 6 534.2 Hydrochloride 56.1 ±11.2 444 14 7 542.3 Trifluoroacetate 83.8 ± 11.4 445 14 8 484.3Hydrochloride 74.5 ± 14.1 446 4 3 518.5 Hydrochloride 64.0 ± 6.0

Example 447

[0232]

[0233] A solution of Amine 4 (300 mg, 1.130 mmol) and trimethylsilylacetamide (TMSA) (210 mg, 1.614 mmol) is dissolved in acetonitrile (1.5mL) and stirred for 30 minutes. To this solution is added Epoxide 62(250 mg, 1.076 mmol) in acetonitrile (3 mL) and ytterbium triflate (13mg, 0.215 mmol). The solution is heated at 80° C. for 24 hours andconcentrated in vacuo. The resulting solid is purified by flash columnchromatography (99% dichloromethane:1% methanol gradient to (95%dichloromethane:5% methanol as eluent) to give 135 mg of the titlecompound (25%). FDMS m/e=500 (M⁺+1). Emax (±SEM)=74.5 (4.0).

Example 448

[0234]

[0235] The compound of Example 346 is hydrolized with 1.0 equivalent oflithium hydroxide (1M), in tetrahydrofuran at room temperatureovernight, and then concentrated to a crude residue which is purifiedvia HPLC as the trifluoroacetic acid salt as described above inRepresentative Procedure 2 and 3. MS 562.2. Emax (±SEM)=79.9 (5.5).

Example 449

[0236]

[0237] The title compound is prepared from the compound of Example 345as described in Example 448. MS 562.2. Emax (±SEM)=74.2 (2.2).

Example 450

[0238]

[0239] The compound of Example 345 in dimethylformamide is treated with1.0 equivalent of sodium ethoxide and 4.0 equivalents of formamide. Themixture is heated to 100° C. for 4 hours, cooled to room temperaturethen concentrated. The residue is purified via HPLC as thetrifluoroacetic acid salt as described above in Representative Procedure2 and 3. MS 561.2. Emax (±SEM)=67.4 (2.1).

Example 451

[0240]

[0241] The compound of Example 50 (250 mg) and 0.5 molar equivalents (29mg) of fumaric acid are suspended in 5 mL of ethanol denatured withtoluene and the mixture is heated mildly to effect dissolution. Afterapproximately five minutes, the solution begins to precipitate. Thetemperature of the crystal slurry is maintained at the crystallizationtemperature (56-57° C.) for about one hour. The heat source is thenturned off and the slurry is allowed to cool with stirring overnight.Ethanol denatured with toluene (2 mL) is added and the solids areisolated by vacuum filtration. The filter cake is washed with ethanoldenatured with toluene (5 mL) and air dried to give 230 mg of the titlecompound. mp=147-149° C. (measured by differential scanning calorimetry(DSC) with a scan rate of 10° C./minute).

Example 452

[0242]

[0243] The compound of Example 50 (57.7 mg) is dissolved in 2.5 mL ofabsolute ethanol and the solution is stirred at room temperature. To thestirred solution is added benzoic acid (1 equivalent, 14.1 mg) dissolvedin 200 microliters of methanol. The resulting mixture is stirred at roomtemperature for 3.5 to 4 hours. Precipitation occurrs in approximately30-60 minutes. The precipitate is isolated by vacuum filtration and thefilter cake is collected and air-dried overnight. mp=148-150° C.(measured by DSC with a scan rate of 5° C./minute).

Example 453

[0244]

[0245] The compound of Example 50 (200 mg) is dissolved in 1 mL ofacetone and the solution is stirred at room temperature. To the stirredsolution is added R-mandelic acid (1 equivalent, 61 mg) in acetone (1ml). The resulting, mixture is stirred at room temperature and theprecipitate is isolated by vacuum filtration. The filter cake iscollected and air dried overnight. mp=138-140 ° C. (measured by DSC witha scan rate of 5° C./minute).

Example 454

[0246]

[0247] The compound of Example 50 (106 mg) is dissolved in 1 mL of ethylacetate and the solution is stirred at room temperature. To the stirredsolution is added salicylic acid (1 equivalent, 29 mg) in 150microliters of methanol. The resulting mixture is stirred at roomtemperature and then heated up to 50° C. Hexane is added to the mixtureas an antisolvent at elevated temperature until cloud point(approxiamtely 1 ml ethyl acetate:l ml of hexane). The slurry is allowedto slowly cool to room temperature. The precipitate is isolated byvacuum filtration and the filter cake is collected and air driedovernight. mp=124° C. (peak max) (measured by DSC with a scan rate of 5°C./minute).

[0248] Demonstration of Function

[0249] The genes encoding the human β₁-adrenergic receptor (Frielle etal., Proc. Natl. Acad. Sci., 84:7920-7924, 1987), the humanβ₂-adrenergic receptor (Kobika et al., Proc. Natl. Acad. Sci., 84:46-50,1987, Emorine et al., Proc. Natl. Acad. Sci., 84:6995-6999, 1987) andthe human β3 adrenergic receptor (Granneman et al., MolecularPharmacology, 44(2):264-70, 1993) are individually subcloned into a phdexpression vector (Grinnell et al., Bio/Technology, 5:1189-1192, 1987)and transfected into the DXB-11 Chinese hamster ovary (CHO) cell line bycalcium phosphate precipitation methodology. The stably transfectedcells are grown to 95% confluency in 95% Dulbecco's modified EaglesMedium (DMEM), 5% fetal bovine serum and 0.01% proline. Media is removedand the cells are washed with phosphate buffered (pH 7.4) saline(without magnesium and calcium). Cells are then lifted using an enzymefree cell dissociation solution (Specialty Media, Lavallette, N.J.) andpelleted by centrifugation.

[0250] Cells from each of the above cell lines are resuspended and added(20,000/well) to a 96-well plate. Cells are incubated at 37° C. withrepresentative compounds of the invention for 20 minutes in buffer(Hank's balanced salt solution, 10 mM HEPES, 0.1% BSA, 1 mM L-ascorbicacid, 0.2% dimethyl sulfoxide, 1 mM 3-isobutyl-1-methylxanthine, pH7.4). After halting the incubation with quench buffer (50 mM Na Acetate,0.25% Triton X-100, pH 5.8), the c-AMP level is quantified byscintillation proximity assay (SPA) using a modification of thecommercially available c-AMP kit (Amersham, Arlington Heights, Ill.)with rabbit anti-cAMP antibody (ICN Biomedicals, Aurora, Ohio) for thekit.

[0251] Sigmoidal dose response curves, from the whole cell receptorcoupled c-AMP assay are fit to a four parameter logistic equation usingnon linear regression: y=(a−d)/(1+(Dose/c)^(b))+d where a and d areresponses at zero and maximal dose, b is the slope factor and c is theEC₅₀ as previously described (DeLean et al., Am. J. Physiol., 235,E97-E102, 1978). EC₅₀ is assessed as the concentration producing 50% ofthe maximum response to each agonist.

[0252] Isoproterenol is accepted in the art as a non-selective β₃agonist and is widely used as a comparator-in evaluating the activity ofcompounds. See Trends in Pharm. Sci., 15:3, 1994. The % intrinsicactivity (E_(max)) of representative compounds of the invention isassessed relative to isoproterenol by the compound's maximal responsedivided by the isoproterenol maximal response times 100.

[0253] In vitro Rat Atrial Tachycardia

[0254] Male rats (250-350 g) (Harlan Sprague Dawley, Indianapolis, Ind.,USA) are killed by cervical dislocation. Hearts are removed and the leftand right atria are dissected and mounted with thread in tissue bathscontaining 10 mls of modified Krebs' solution. Initial resting tensionis 1.5-2.0 g at the outset of the experiment (Naunyn-Schmied Arch.Pharmacol., 320:145, 1982). Tissues are allowed to equilibrateapproximately 30 minutes with vigorous oxygenation before exposure to acompound of the invention.

[0255] To evaluate the ability of test compounds to increase heart rate,representative compounds of the present invention are added cumulativelyonce the atrial rate reached a steady state from the previous addition.Compound addition is continued until no further increase in atrial rateoccurred or until a concentration of 10⁻⁴M is reached. The increase inbeats per minute (bpm) is measured for each concentration of testcompound by means of a BioPac System (Br. J. of Pharmacol.,126:1018-1024, 1999).

[0256] Utilities

[0257] As agonists of the β₃ receptor, a compound of the presentinvention is useful in treating conditions in human and non-humananimals in which the β₃ receptor has been demonstrated to play a role.The diseases, disorders or conditions for which compounds of the presentinvention are useful in treating or preventing include, but are notlimited to, (1) diabetes mellitus, (2) hyperglycemia, (3) obesity, (4)hyperlipidemia, (5) hypertriglyceridemia, (6) hypercholesterolemia, (7)atherosclerosis of coronary, cerebrovascular and peripheral arteries,(8) gastrointestinal disorders including peptid ulcer, esophagitis,gastritis and duodenitis, (including that induced by H. pylori),.intestinal ulcerations (including inflammatory bowel disease, ulcerativecolitis, Crohn's disease and proctitis) and gastrointestinalulcerations, (9) neurogenic inflammation of airways, including cough,asthma, (10) depression, (11) prostate diseases such as benign prostatehyperplasia, (12) irritable bowel syndrome and other disorders needingdecreased gut motility, (13) diabetic retinopathy, (14) neuropathicbladder dysfunction, (15) elevated intraocular pressure and glaucoma and(16) non-specific diarrhea dumping syndrome.

[0258] In treating non-human, non-companion animals, the compounds ofthe present invention are useful for increasing weight gain and/orimproving the feed utilization efficiency and/or increasing lean bodymass and/or decreasing birth mortality rate and increasing post/natalsurvival rate.

[0259] Formulation

[0260] The compound of formula I is preferably formulated in a unitdosage form prior to administration. Therefore, yet another embodimentof the present invention is a pharmaceutical formulation comprising acompound of formula I and a pharmaceutical carrier.

[0261] The present pharmaceutical formulations are prepared by knownprocedures using well-known and readily available ingredients. In makingthe formulations of the present invention, the active ingredient(formula I compound) will usually be mixed with a carrier, or diluted bya carrier, or enclosed within a carrier which may be in the form of acapsule, sachet, paper or other container. When the carrier serves as adiluent, it may be a solid, semisolid or liquid material which acts as avehicle, excipient or medium for the active ingredient. Thus, thecompositions can be in the form of tablets, pills, powders, lozenges,sachets, cachets, elixirs, suspensions, emulsions, solutions, syrups,aerosol (as a solid or in a liquid medium), soft and hard gelatincapsules, suppositories, sterile injectable solutions and sterilepackaged powders.

[0262] Some examples of suitable carriers, excipients, and diluentsinclude lactose, dextrose, sucrose, sorbitol, mannitol, starches, gumacacia, calcium phosphate, alginates, tragacanth, gelatin, calciumsilicate, microcrystalline cellulose, polyvinylpyrrolidone, cellulose,water syrup, methyl cellulose, methyl and propylhydroxybenzoates, talc,magnesium stearate and mineral oil. The formulations can additionallyinclude lubricating agents, wetting agents, emulsifying and suspendingagents, preserving agents, sweetening agents or flavoring agents. Thecompositions of the invention may be formulated so as to provide quick,sustained or delayed release of the active ingredient afteradministration to the patient.

Formulation Examples Formulation 1 Tablets

[0263] Ingredient Quantity (mg/tablet) Active Ingredient  5-500Cellulose, microcrystalline 200-650  Silicon dioxide, fumed 10-650Stearate acid 5-15

[0264] The components are blended and compressed to form tablets.

Formulation 2 Suspensions

[0265] Ingredient Quantity (mg/5 ml) Active Ingredient 5-500 mg Sodiumcarboxymethyl cellulose 50 mg Syrup 1.25 mg Benzoic acid solution 0.10ml Flavor q.v. Color q.v. Purified water to 5 ml

[0266] The medicament is passed through a No. 45 mesh U.S. sieve andmixed with the sodium carboxymethyl cellulose and syrup to form a smoothpaste. The benzoic acid solution, flavor, and color are diluted withsome of the water and added, with stirring. Sufficient water is thenadded to produce the required volume.

Formulation 3 Intravenous Solution

[0267] Ingredient Quantity Active Ingredient   25 mg Isotonic saline1,000 ml

[0268] The solution of the above ingredients is intravenouslyadministered to a patient at a rate of about 1 ml per minute.

[0269] Dose

[0270] The specific dose administered is determined by the particularcircumstances surrounding each situation. These circumstances include,the route of administration, the prior medical history of the recipient,the pathological condition or symptom being treated, the severity of thecondition/symptom being treated, and the age and sex of the recipient.However, it will be understood that the therapeutic dosage administeredwill be determined by the physician in the light of the relevantcircumstances.

[0271] Generally, an effective minimum daily dose of a compound offormula I is about 5, 10, 15, or 20 mg. Typically, an effective maximumdose is about 500, 100, 60, 50, or 40 mg. Most typically, the doseranges between 15 mg and 60 mg. The exact dose may be determined, inaccordance with the standard practice in the medical arts of “dosetitrating” the recipient; that is, initially administering a low dose ofthe compound, and gradually increasing the does until the desiredtherapeutic effect is observed.

[0272] Route of Administration

[0273] The compounds can be administered by a variety of routesincluding the oral, rectal, transdermal, subcutaneous, topical,intravenous, intramuscular or intranasal routes.

[0274] Combination Therapy

[0275] A compound of formula I may be used in combination with otherdrugs that are used in the treatment/prevention/suppression oramelioration of the diseases or conditions for which compounds offormula I are useful. Such other drug(s) may be administered, by a routeand in an amount commonly used therefor, contemporaneously orsequentially with a compound of formula I. When a compound of formula Iis used contemporaneously with one or more other drugs, a pharmaceuticalunit dosage form containing such other drugs in addition to the compoundof formula I is preferred. Accordingly, the pharmaceutical compositionsof the present invention include those that also contain one or moreother active ingredients, in addition to a compound of formula I.Examples of other active ingredients that may be combined with acompound of formula I, either administered separately or in the samepharmaceutical compositions, include, but are not limited to:

[0276] (a) insulin sensitizers including (i) PPARγ agonists such as theglitazones (e.g. troglitazone, pioglitazone, englitazone, MCC-555,BRL49653 and the like), and compounds disclosed in WO97/27857, 97/28115,97/28137 and 97/27847; (ii) biguanides such as metformin and phenformin;

[0277] (b) insulin or insulin mimetics;

[0278] (c) sulfonylureas such as tolbutamide and glipizide;

[0279] (d) alpha-glucosidase inhibitors (such as acarbose);

[0280] (e) cholesterol lowering agents such as

[0281] i. HMG-CoA reductase inhibitors (lovastatin, simvastatin andpravastatin, fluvastatin, atorvastatin, and other statins),

[0282] ii. sequestrants (cholestyramine, colestipol and adialkylaminoalkyl derivatives of a cross-linked dextran),

[0283] iii. nicotinyl alcohol nicotinic acid or a salt thereof,

[0284] iv. proliferator-activator receptor a agonists such as fenofibricacid derivatives (gemfibrozil, clofibrat, fenofibrate and benzafibrate),

[0285] v.inhibitors of cholesterol absorption for examplebeta-sitosterol and (acyl CoA:cholesterol acyltransferase) inhibitorsfor example melinamide,

[0286] vi. probucol,

[0287] vii. vitamin E, and

[0288] viii. thyromimetics;

[0289] (f) PPARδ agonists such as those disclosed in WO97/28149;

[0290] (g) antiobesity compounds such as fenfluramine, dexfenfluramine,phentermine, sibutramine, orlistat, and other β₃ adrenergic receptoragonists;

[0291] (h) feeding behavior modifying agents such as neuropeptide Yantagonists (e.g. neuropeptide Y5) such as those disclosed in WO97/19682, WO 97/20820, WO 97/20821, WO 97/20822 and WO 97/20823;

[0292] (i) PPARα agonists such as described in WO 97/36579 by Glaxo;

[0293] (j) PPARγ antagonists as described in WO97/10813; and

[0294] (k) serotonin reuptake inhibitors such as fluoxetine andsertraline.

1. A compound of formula I:

wherein: A¹, A² and A³ are carbon or nitrogen provided that only one ofA¹, A² and A³ is nitrogen; Het is an optionally substituted, optionallybenzofused 5 or 6 membered heterocyclic ring; R¹, R^(1a) and R^(1b) areindependently H, halo, hydroxy, C₁-C₆ alkyl, C₁-C₆ alkoxy, C₁-C₄haloalkyl, or SO₂(C₁-C₆ alkyl); R² is H or C₁-C₆ alkyl; R³ is H or C₁-C₆alkyl; R⁴ is H or C₁-C₆ alkyl; or R³ and R⁴ combine with the carbon towhich both are attached to form a C₃-C₆ cyclic ring; or R⁴ and X¹combine with the carbon to which both are attached to form a C₃-C₈cyclic ring; or R⁴ combines with X¹, the carbon to which both areattached, and the phenyl group to which X¹ is attached to form:

wherein: n and m are independently 0, 1, 2, or 3 provided that the sumof n+m is≦4 and that R³ is H; X is OCH₂, SCH₂ or a bond; X¹ is a bond ora C₁-C₅ divalent hydrocarbon moiety; X² is O, S, NH, NHSO₂, SO₂NH, CH₂or a bond; and X³ is optionally substituted phenyl or an optionallysubstituted 5 or 6 membered heterocyclic ring; or a pharmaceutical saltthereof.
 2. The compound of claim 1 wherein: A¹, A² and A³ are carbon;Het is optionally substituted one to three times independently withhalo, hydroxy, oxo, cyano, nitro, phenyl, benzyl, C₁-C₄ alkyl, C₁-C₄haloalkyl, C₁-C₄ alkoxy, COR⁸, CO₂R⁸, CONR⁸R⁸, NR⁸R⁸, NHCO(C₁-C₄ alkyl),NHCO(phenyl), NHCO(benzyl), SR⁸, SO(C₁-C₄ alkyl), SO₂(C₁-C₄ alkyl),SO₂(NR⁸R⁸), OCO(C₁-C₄ alkyl), OCO₂R⁸ or OCONR⁸R⁸ R¹, R^(1a) and R^(1b)are independently H, halo, C₁-C₄ alkyl, C₁-C₄ alkoxy, C₁-C₄ haloalkyl,or SO₂(C₁-C₄ alkyl); R² is H or C₁-C₄ alkyl; R³ and R⁴ are independentlyH or C₁-C₄ alkyl; or R³ and R⁴ combine with the carbon to which both areattached to form a C₃-C₆ cyclic ring; or R⁴ and X¹ combine with thecarbon to which both are attached to form a C₃-C₈ cyclic ring; or R⁴combines with X¹, the carbon to which both are attached, and the phenylgroup to which X¹ is attached to form:

X³ is optionally substituted one to three times independently with halo,hydroxy, oxo, cyano, nitro, phenyl, benzyl, C₁-C₄ alkyl, C₁-C₄haloalkyl, C₁-C₄ alkoxy, COR⁸, CO₂R⁸, CONR⁸R⁸, NR⁸R⁸, NHCO(C₁-C₄ alkyl),NHCO(phenyl), NHCO(benzyl), SR⁸, SO(C₁-C₄ alkyl), SO₂(C₁-C₄ alkyl),SO₂(NR⁸R⁸), OCO(C₁-C₄ alkyl), OCO₂R⁸ or OCONR⁸R⁸; and R⁸ isindependently at each occurrence H or C₁-C₄ alkyl; or a pharmaceuticalsalt thereof.
 3. The compound of claim 2 of the formula:

wherein: Het is selected from furan; isothiazole; isoxazole; oxazole;and thiophene; wherein said Het moieties are optionally substituted oncewith fluorine, methyl, cyano, SO₂NH₂ or COCH₃; R³ and R⁴ areindependently H or methyl; X³ is phenyl, pyridyl or pyridazinyl whereinsaid X³ moieties are substituted once or twice with chloro, cyano, CONH₂or SO₂CH₃; or a pharmaceutical salt thereof.
 4. The compound of claim 3wherein Het is thien-2-yl optionally substituted once with fluorine,methyl, cyano, SO₂NH₂ or COCH₃; R³ and R⁴ are both methyl; and X³ isphenyl or pyridyl wherein said X³ moieties are substituted once withcyano or CONH₂; or a pharmaceutical salt thereof.
 5. The compound ofclaim 4 wherein X³ is pyridyl substituted once with cyano or CONH₂; or apharmaceutical salt thereof.
 6. The compound of claim 5 which isselected from the group consisting of:

or a pharmaceutical salt thereof.
 7. A compound of the formula:

or a pharmaceutical salt thereof.
 8. The compound of claim 7 which isthe hydrochloride salt.
 9. The compound of claim 7 which is thehemi-fumarate, benzoate, salicylate or R-mandelate salt.
 10. Cancelled11. A method of treating obesity comprising administering to a patientin need thereof a compound of claim
 3. 12. A method of treating Type IIDiabetes comprising administering to a patient in need thereof acompound of claim
 3. 13. Cancelled
 14. Cancelled
 15. A compound offormula II:

wherein: A¹, A² and A³ are carbon or nitrogen provided that only one ofA¹, A² and A³ is nitrogen; Het is an optionally substituted, optionallybenzofused 5 or 6 membered heterocyclic ring; R¹ and R^(1a) areindependently H, halo, hydroxy, C₁-C₆ alkyl, C₁-C₆ alkoxy, C₁-C₆haloalkyl, or SO₂ (C₁-C₆ alkyl); or a salt thereof.
 16. The compound ofclaim 15 of the formula:

wherein: Het is selected from benzothiophene; furan; isothiazole;isoxazole; oxazole; thiophene; and thiazole; wherein said Het moietiesare optionally substituted once with fluorine, chlorine, methyl, cyano,SO₂NH₂ or COCH₃; or a salt thereof.
 17. A process for preparing acompound of claim 1 which comprises reacting a compound of formula II:

with a compound of formula III:

in the presence of a suitable solvent.
 18. A method of treating obesitycomprising administering to a patient in need thereof a compound ofclaim
 7. 19. A method of treating obesity comprising administering to apatient in need thereof a compound of claim
 8. 20. A method of treatingobesity comprising administering to a patient in need thereof a compoundof claim 9.